CN105384792B - Compounds as Hepatitis C Inhibitors and Their Use in Medicines - Google Patents

Abstract

The invention provides a compound shown as a formula (I) or a stereoisomer, a geometric isomer, a tautomer, an enantiomer, a nitrogen oxide, a hydrate, a solvate, a metabolite and a pharmaceutically acceptable salt or prodrug of the compound shown as the formula (I), which is used for treating Hepatitis C Virus (HCV) infection or hepatitis C diseases. Also disclosed are pharmaceutical compositions containing such compounds and methods of using the compounds or pharmaceutical compositions of the invention to treat HCV infection or hepatitis C disease.

Description

Compounds as Hepatitis C Inhibitors and Their Use in Medicines

Field of Invention

The present invention belongs to the field of medicine, and particularly relates to compounds for treating hepatitis C virus (HCV) infection, compositions of the compounds, and uses and methods of use thereof. In particular, the compounds of the present invention are useful for inhibiting NS3/4A protease. More specifically, the present invention relates to compounds that can inhibit the function of the NS3/4A protein encoded by the hepatitis C virus, pharmaceutical compositions of the compounds, and methods for inhibiting the function of the NS3/4A protein.

Background of the Invention

HCV is the major human pathogen, infecting an estimated 170 million people globally, five times the number infected with human immunodeficiency virus type 1. The majority of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Therefore, chronic HCV infection will be the leading cause of premature death due to liver disease in patients worldwide.

Currently, the most effective HCV therapy is the combination of alpha-interferon and ribavirin, which produces sustained efficacy in 40% of patients. Recent clinical results suggest that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy. However, even with experimental regimens including a combination of pegylated alpha-interferon and ribavirin, most patients did not achieve sustained reductions in viral load, and many patients were often accompanied by side effects that prevented long-term treatment . Therefore, new and effective treatments for HCV infection are urgently needed.

HCV is a positive-strand RNA virus. Based on a comparison of the deduced amino acid sequence and the broad similarity of the 5' untranslated region, HCV is classified into a separate genus of the Flaviviridae family. All members of the Flaviviridae family are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins through translation of a single uninterrupted open reading frame (ORF).

There is considerable heterogeneity within the nucleotide and encoded amino acid sequences throughout the HCV genome. At least 7 major genotypes have been identified, and more than 50 subtypes have been disclosed. In HCV-infected cells, viral RNA is translated into polyproteins and split into 10 individual proteins. At the amino terminus are structural proteins, followed by E1 and E2. In addition, there are six nonstructural proteins, namely NS2, NS3, NS4A, NS4B, NS5A, and NS5B, which play very important roles in the HCV life cycle (see, eg, Lindenbach, B.D. and C.M. Rice, Nature. 436, 933 -938, 2005).

The major genotypes of HCV are distributed differently globally, and despite numerous studies on the pathogenesis and therapeutic effects of genotypes, the clinical importance of HCV genetic heterogeneity remains unclear.

The single-stranded HCV RNA genome is approximately 9500 nucleotides in length with a single open reading frame, encoding a single large polyprotein of approximately 3000 amino acids. In infected cells, the polyprotein is cleaved at multiple sites by cellular and viral proteases, resulting in structural and nonstructural (NS) proteins. In the case of HCV, the formation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is accomplished by two viral proteases. The first is generally believed to be a metalloprotease that cleaves at the NS2-NS3 junction; the second is a serine protease contained in the N-terminal region of NS3 (also referred to herein as NS3 protease), which mediates all subsequent cleavage downstream of NS3, It is in cis at the NS3-NS4A cleavage site, and in trans at the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NA5B sites. The NS4A protein appears to have multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in membrane localization of NS3 and other viral replicase components. Formation of the NS3 protein in complex with NS4A appears to be a processing event required for increased proteolytic efficiency at all sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV replication.

The compounds of the present invention are used to treat HCV infection in patients, and the compounds selectively inhibit the replication of HCV virus. Specifically, the compounds of the present invention are compounds that effectively inhibit the function of the NS3/4A protein.

Summary of Invention

The present invention relates to a macrocyclic compound and a method for anti-HCV infection. The compounds or pharmaceutical compositions of the present invention have a good inhibitory effect on HCV infection, especially on HCV NS3/4A protein.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, enantiomer of the compound represented by formula (I) Forms, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

wherein: Ring A and Ring B are each independently a cycloalkyl, heterocyclyl, aryl or heteroaryl group;

Each R ¹ and R ² is independently H, deuterium, hydroxyl, F, Cl, Br, I, N ₃ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , - C(=O)OR ⁵ , -C(=O)R ⁵ , -N(R ⁷ )S(=O) ₂ R ⁵ , -N(R ⁷ )S(=O) ₂ NR ⁷ R ¹¹ , - S(=O) ₂ NR ⁷ R ¹¹ , -C(=O)NR ⁷ R ¹¹ , -N(R ⁷ )C(=O)R ⁵ , cyano, nitro, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, alkylthio, cycloalkyl, cycloalkyl-O-, heterocyclyl, aryl or heteroaryl;

^R3 and ^R4 are each independently H, deuterium, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl cycloalkyl, aryl or heteroaryl;

L is -C(=O)-, -OC(=O)-, -C(=S)-, -OC(=S)-, -N(R ⁷ )C(=S)- or -N( R ⁷ )C(=O)-;

表示-X或＝X；当

为-X时，X为CR⁵R⁶、NR⁷、O或S；当

为＝X时，X为CR⁵或N；

means -X or =X; when

When -X, X is CR ⁵ R ⁶ , NR ⁷ , O or S; when

When =X, X is CR ⁵ or N;

Y is -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S- or -S(=O) _t -;

T is -CR ⁵ R ⁶ -, -O-, -S-, -NR ⁷ -, -CH ₂ O-, -OS(=O) _t -, -OC(=O)-, -OC(=O )N(R ⁷ )- or -N(R ⁷ )C(=O)-;

W is CR ⁵ or N;

Q is -(CR ⁵ R ⁶ ) _p -Z-(CR ⁸ R ⁹ ) _q -;

Z is a bond, -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S-, -S(=O) _t -, -C(=O)-, -OC(=O)-, -OC(=O)N(R ⁷ )-, -N(R ⁷ )C(=O)-, -C(=O)N(R ⁷ )-, alkenylene, alkynylene, cycloalkane radical, heterocyclylene, arylene, arylene-O, arylene-O, arylene-S, arylene-N, or heteroarylene;

Each ^R5 , R6, ^R8 and ^R9 is independently H, deuterium, hydroxy, amino, F, ^Cl , Br, I, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl or Heteroaryl;

Each ^R7 and ^R11 is independently H, deuterium, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

m and n are each independently 0, 1, 2, 3 or 4;

each t is independently 1 or 2;

p and q are each independently 0, 1, 2, 3, 4 or 5;

表示

或

express

or

The above-mentioned alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyl-O-, haloalkyl, haloalkoxy, heterocyclyl, aryl , heteroaryl, alkenylene, cycloalkylene, heterocyclylene, heterocycloalkylene, arylene, heteroarylene-O, heteroarylene-O, arylene-S, arylene Aryl-N and heteroarylene are independently optionally replaced by 1, 2, 3 or 4 selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents.

In some embodiments, wherein Ring A and Ring B are each independently a _C3-10 cycloalkyl, _C2-10 heterocyclyl, _C6-10 aryl, or _C1-9 heteroaryl group;

Each R ¹ and R ² is independently H, deuterium, hydroxy, F, Cl, Br, I, N ₃ , amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyl -O-, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

为＝X时，X为CR⁵或N；

When =X, X is CR ⁵ or N;

Y is -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S- or -S(=O) _t -;

Each R ⁵ and R ⁶ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, or C _{2- 6} alkynyl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

m and n are each independently 0, 1, 2, 3 or 4;

The above-mentioned C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-10 cycloalkyl, C _{1 -6} haloalkyl, C _1-6 haloalkoxy, C _2-10 heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl independently optionally selected from 1, 2, 3 or 4 Deuterium, hydroxyl, F, Cl, Br, I, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C Substituents of _1-6 alkylamino, C _3-10 cycloalkyl, C _6-10 aryl, C _1-9 heteroaryl or C _2-10 heterocyclyl.

In other embodiments, wherein Ring A and Ring B are each independently phenyl, pyridyl, thiazolyl, oxazolyl, imidazolyl, furyl, thienyl, pyrazolyl, isoxazolyl, pyrrole group, quinolinyl, indolyl or naphthyl group.

In some embodiments, wherein L is -C(=O)-, -OC(=O)- or -NHC(=O)-;

R ⁴ is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl, C _{2- 10} heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano , nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _{1 -6} alkylamino, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl substituent.

^In some embodiments, wherein Q is ^- ( ^CR5R6 ) _p -Z-( ^CR8R9 ) _q- ;

Z is a bond, -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S-, -S(=O) ₂ -, C _2-6 alkenylene, C _2-6 alkynylene, C _3-10 cycloalkylene, C _2-10 heterocyclylene, C _6-10 arylene, C _6-10 arylene-O, C _6-10 arylene-S, C _6-10 Arylene-N or C _1-9 heteroarylene;

Each of R ⁵ , R ⁶ , R ⁸ and R ⁹ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane oxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

p and q are each independently 0, 1, 2, 3, 4 or 5.

In some embodiments, wherein R ³ is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkane base C _1-6 alkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl, C _{2- 10} heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano , nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _{1 -6} alkylamino, C _3-6 cycloalkyl, C _2-6 heterocycloalkyl, C _6-10 aryl or C _1-9 heteroaryl substituent.

为In some embodiments, wherein

for

each of A ¹ and A ² is independently CR ¹⁰ or N;

A ³ is CR ⁵ R ⁶ , NR ⁷ , O or S;

Each R ¹ and R ² is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, N ₃ , cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyl -O-, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁵ and R ⁶ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

Each R ¹⁰ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy group, C _2-6 alkenyl or C _2-6 alkynyl;

wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _1-6 Haloalkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkane-O, C _2-10 heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl are independently optionally replaced by 1, 2, 3 or 4 are selected from deuterium, hydroxyl, F, Cl, Br, I, amino, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _6-10 aryl substituted with substituents of C 1-9 heteroaryl or C _1-9 heteroaryl.

为In other embodiments, wherein

for

In some embodiments, it has a structure as shown in formula (I'),

Or stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable compounds of the compound represented by formula (I') salt or prodrug;

为in,

for

each of A ¹ and A ² is independently CR ¹⁰ or N;

A ³ is CR ⁵ R ⁶ , NR ⁷ , O or S;

Each R ¹ and R ² is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, N ₃ , cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl -O, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁵ and R ⁶ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _{2- 6} alkynyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

Each R ¹⁰ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy group, C _2-6 alkenyl or C _2-6 alkynyl;

wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _{1-6 6} haloalkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl, C _1-6 alkyl, C _2-10 heterocyclyl, C _3-8 cycloalkane-O, C _6-10 aryl and C _1-9 heteroaryl independently optionally by 1, 2, 3 or 4 selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylamino, C _3-6 cycloalkane substituted with substituents of C 2-6 heterocyclyl or C _2-6 heterocyclyl.

In other embodiments, wherein each A ¹ and A ² is independently CR ¹⁰ or N;

A ³ is NH, O or S;

Each ^R10 is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, ethynyl, trifluoromethyl or trifluoro methoxy;

Each R1 and ^R2 is independently H, deuterium, hydroxy, F, Cl, Br, ^I , amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclo Amyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyclopropyloxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazole radical, furyl, imidazolyl, thienyl, pyrazolyl, isoxazolyl, indolyl, naphthyl, ethynyl, vinyl, propynyl or propenyl;

The above-mentioned methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, cyclopropyloxy, trifluoro Methyl, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, pyrazolyl, isoxazolyl, indolyl, naphthyl, ethynyl, vinyl, Propynyl and propenyl are independently optionally replaced by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, methyl, ethyl, isopropyl, butyl, tert-butyl, Substituents of methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, trifluoromethyl or trifluoromethoxy.

为In other embodiments, wherein,

for

In other embodiments, wherein R ³ and R ⁴ are each independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _2-10 heterocyclyl, C _{6 -10} aryl and C _1-9 heteroaryl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C _{1- 4} alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylamino, C _{3 -6} cycloalkyl, _C2-6 heterocyclyl, _C6-10 aryl or _C1-9 heteroaryl substituent.

^In other embodiments, wherein ^R3 and R4 are each independently H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, morpholinyl, piperazinyl, pyrazinyl, piperidinyl, phenyl, propenyl, propynyl, oxazole radical, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, furanyl, thienyl or pyridyl;

The methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, Cyclohexenyl, morpholinyl, piperazinyl, pyrazinyl, piperidinyl, phenyl, propenyl, propynyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl , thiazolyl, triazolyl, furanyl, thienyl, and pyridyl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl , isopropyl, butyl, tert-butyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, trifluoromethyl or trifluoromethoxy substituent.

In other embodiments, wherein T is -O-, -S- or ^-NR7- ;

^R7 is H, deuterium, F, Cl, Br, I, methyl, ethyl, isopropyl or trifluoromethyl.

In other embodiments, wherein W is CH or N.

^In other embodiments, wherein Q is ^- ( ^CR5R6 ) _p -Z-( ^CR8R9 ) _q- ;

Z is a bond, -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S-, -S(=O) ₂ -, C _2-6 alkenylene, C _2-6 alkynylene, C _3-8 cycloalkylene, C _2-10 heterocyclylene, C _6-10 arylene, C _6-10 arylene-O or C _1-9 heteroarylene;

Each R ⁵ , R ⁶ , R ⁸ and R ⁹ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkyne base;

R ⁷ is H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl or C _6-10 aryl;

p and q are each independently 0, 1, 2, 3, 4 or 5;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _{6 -10} aryl, C _2-6 alkenylene, C _2-6 alkynylene, C _3-8 cycloalkylene, C _2-10 heterocyclylene, C _6-10 arylene, C _{6- 10} Arylene-O and C _1-9 Heteroarylene independently optionally by 1, 2, 3 or 4 selected from H, deuterium, hydroxyl, F, Cl, Br, I, amino, cyano, nitro base, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 Substituents of alkylamino, C _3-6 cycloalkyl or C _2-6 heterocyclyl.

In other embodiments, Z is a bond, _-CH2- , ^-NR7- , -O-, -S-, -S(=O) _2- , vinylene, ethynylene, cyclopropylene , cyclobutylene, cyclopentylene, cyclohexylene, phenylene-O, phenylene-S, thiazolylidene, imidazolylidene, or phenylene;

Each of ^R5 , R6, ^R8 and ^R9 is independently H, deuterium, hydroxy, F, ^Cl , Br, I, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl , vinyl or ethynyl;

R ⁷ is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

The methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinylidene, Ethynyl, cyclopropylidene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene-S, thiazolylylene, imidazolylide, phenylene-O, and phenylene can be independently optionally Substituted with 1, 2, 3 or 4 substituents selected from H, deuterium, F, Cl, Br, I, amino, methyl, methoxy, hydroxy, nitro, cyano.

为In other embodiments, wherein,

for

Each R1 and R2 is independently H, deuterium, hydroxy, F, Cl, Br, ^I , amino, cyano, nitro, methyl, ethyl, isopropyl, butyl, tert ^- butyl, cyclopropyl base, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxa azolyl, furanyl, imidazolyl, thienyl, indolyl, naphthyl, ethynyl, vinyl, propynyl or propenyl;

n is 0, 1, 2, 3 or 4;

The above-mentioned methyl, ethyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, tri Fluoromethyl, trifluoromethoxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, indolyl, naphthyl, ethynyl, vinyl, propyne and propenyl are independently optionally replaced by 1, 2, 3 or 4 groups selected from H, deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, methoxy, ethylene group, ethynyl, trifluoromethyl or trifluoromethoxy substituent.

In another aspect, the present invention provides a pharmaceutical composition comprising any one of the above compounds; or further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or the like combination.

In some embodiments, it further comprises other anti-HCV drugs; wherein the anti-HCV drugs are interferon, ribavirin, interleukin-2, interleukin-6, interleukin-12, promoting the production of type 1 adjuvant T-cell responsive compounds, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, baviximab ( Bavituximab), Civacir ^™ , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir (danoprevir), ciluprevir (ciluprevir), narlaprevir (narlaprevir), deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir ( ABT-267), neceprevir(ACH-2684), tegobuvir(GS-9190), grazoprevir(MK-5172), sovaprevir(ACH-1625), samatasvir(IDX-719), setrobuvir, veruprevir(ABT-450), erlotinib, simeprevir(TMC-435), asunaprevir(BMS-650032), vaniprevir(MK-7009), faldaprevir(BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530 , ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir(GS-9451), BZF-961, GS-9256, ANA975, EDP239, PPI-668, GS-5816, MK-8325, GSK- 2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-3 71, VCH-916, VCH-222, ANA-598, MK-3281, ABT-072, PF-00868554, BI-207127, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha-interferon IFN, interferon gamma, or a combination thereof.

In some embodiments, it further comprises at least one HCV inhibitor for at least one of inhibiting HCV replication process and inhibiting HCV viral protein function; the HCV replication process is selected from HCV entry, The complete viral cycle of HCV unpacked, translated, replicated, assembled or released. The HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV virus replication.

On the other hand, the compound or pharmaceutical composition of the present invention is used to inhibit at least one of HCV replication process and HCV viral protein function; the HCV replication process is selected from HCV entry, uncoating, translation, replication, assembly or the full viral cycle of released HCV. The HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV virus replication.

In another aspect, the present invention relates to the use of a compound or pharmaceutical composition of the present invention for the preparation of a medicament for the prevention, treatment, treatment or alleviation of hepatitis C disease in a patient, comprising administering to the patient an effective amount of a compound as described in the present invention or the present invention The pharmaceutical composition of the invention.

Another aspect of the present invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I) or (I').

The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

Unless otherwise stated, the following definitions as used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry may be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, Its entire contents are incorporated herein by reference.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to one or more than one (ie, at least one) object of the article. For example, "a component" refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.

The term "subject" as used herein refers to an animal. Typically such animals are mammals. A subject, for example, also refers to primates (eg, humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .

"Chiral" is a molecule that has the property of being non-superimposable with its mirror image; while "achiral" refers to a molecule that is superimposable with its mirror image.

"Enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

"Diastereomer" refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

Stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and 1 or (+) and (-) are symbols used to designate the rotation of plane polarized light by the compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms) ) in the form of. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration.

The resulting mixtures of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

Any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, eg, by performing diastereomeric salts thereof obtained. separation. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of NotreDame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds. It is to be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position. When substituents are described as being "independently selected from" groups, each substituent is selected independently of the other, and thus each substituent may be the same or different from each other.

In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and both are interchangeable. It should be understood in a broad sense. It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkyl groups _.

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, _-CH3 ), ethyl (Et, -CH2CH3), n _{- propyl} (n _- Pr, _{-CH2CH2CH3 )} ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH ) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH 2CH2CH2CH2CH3), ₂ -pentyl (-CH( _{CH3 ) CH2CH2CH3 )} , _{3 -} pentyl (-CH( _{CH2CH3 ) 2 )} , ₂ -methyl -2-butyl(-C(CH3)2CH2CH3), ₃ -methyl- _{2-butyl(-CH(CH3)CH(CH3)2 ) , 3 - methyl} -1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH _{2 CH2CH2CH3} ), ₂ -hexyl (-CH( _CH3 ) _{CH2CH2CH2CH3 )} , _{3 -} hexyl (-CH( _{CH2CH3 ) ( CH2CH2CH3 ) )} , 2-Methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

The term "alkylene" refers to a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group A group contains 1-3 carbon atoms; in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Such examples include methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), isopropylidene (-CH( _{CH3 )} CH2- ₎ , and the like.

The term "heteroalkyl" means that one or more heteroatoms may be inserted into the alkyl chain, wherein the alkyl group and the heteroatom have the meanings as described herein. Unless otherwise specified, heteroalkyl groups contain 2-10 carbon atoms, in other embodiments, heteroalkyl groups contain 2-8 carbon atoms, and in other embodiments, heteroalkyl groups contain 2 -6 carbon atoms, in other embodiments, the heteroalkyl group contains 2-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 2-3 carbon atoms. Such examples include, but are not _limited to, _{CH3OCH2- , CH3CH2OCH2- , CH3SCH2-} , _{( CH3 ) 2NCH2-} , _{( CH3 ) 2CH2OCH2-} , _{CH3OCH2CH2- , CH3CH2OCH2CH2- , etc. _ _}

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp ² double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the "cis" and "trans" positions, or the "E" and "Z" positions. In one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH= _CH2 ), allyl (-CH2CH= _{CH2 )} , and the like.

The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), ₁ -propynyl (-C≡C- _CH3 ), and the like .

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3-12 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms carbon atom. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

基、二氮杂

基、硫氮杂

基、吲哚啉基、1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基。杂环基中-CH₂-基团被-C(O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and both refer to saturated or partially unsaturated monocyclic, bicyclic or tricyclic rings containing 3 to 12 ring atoms, at least one of which is selected from the group consisting of Nitrogen, sulfur and oxygen atoms, but at least one of the rings does not belong to the aromatic class. Unless otherwise specified, heterocyclyl groups can be carbon or nitrogen groups, and _-CH2- groups can be optionally replaced by -C(O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. In some embodiments, the heterocyclic group is a C _2-10 heterocyclic group, indicating that the heterocyclic group contains 2-10 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heterocyclic group The group is a C _2-9 heterocyclic group, which means that the heterocyclic group contains 2-9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heterocyclic group is a C _2-7 heterocyclic group Cyclic group, which means that the heterocyclyl group contains 2-7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heterocyclyl group is C _2-5 heterocyclyl group, which means the heterocyclyl group Contains 2-5 carbon atoms and at least one heteroatom selected from O, S and N. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide ring Amyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thio oxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine

base, diazepine

base, thiazepine

base, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5 -base. Examples of heterocyclyl groups where the _-CH2- group is substituted with -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone , 3,5-dioxopiperidyl and pyrimidinedione. Examples of the oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The term "heterocyclylalkyl" includes a heterocyclyl-substituted alkyl group; the term "heterocyclylalkoxy" includes a heterocyclyl-substituted alkoxy group in which the oxygen atom is attached to the remainder of the molecule; the term "heterocyclylalkoxy" "Alkylamino" includes heterocyclyl-substituted alkylamino groups in which the nitrogen atom is attached to the remainder of the molecule. wherein heterocyclyl, alkyl, alkoxy and alkylamino have the meanings as described herein, such examples include, but are not limited to, pyrrol-2-ylmethyl, morpholin-4-ylethyl, Linn-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino and the like.

The term "consisting of n atoms", where n is an integer, typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is n. For example, piperidinyl is a 6-atom heterocycloalkyl group, while 1,2,3,4-tetrahydronaphthalene is a 10-atom cycloalkyl group.

The term "unsaturated" as used herein means that the group contains one or more degrees of unsaturation.

The term "heteroatom" refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or on a nitrogen atom in a heterocyclic ring. Hydrogen substituted form, for example, N (like N in 3,4-dihydro-2H-pyrrolidinyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic A family of rings in which each ring system contains a ring of 3-7 atoms with one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl groups can be independently optionally substituted with one or more substituents described herein.

The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, wherein each ring system contains a ring of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group is a C _1-9 heteroaryl group, which means that the heteroaryl group contains 1-9 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, The heteroaryl group is a C _1-7 heteroaryl group, which means that the heteroaryl group contains 1-7 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heteroaryl group is C _{1 -6} heteroaryl, indicating that the heteroaryl group contains 1-6 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heteroaryl group is a C _1-5 heteroaryl group, Indicates that the heteroaryl group contains 1-5 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heteroaryl group is a C _1-4 heteroaryl group, indicating that the heteroaryl group contains 1 -4 carbon atoms and at least one heteroatom selected from O, S and N; in other embodiments, the heteroaryl group is a C _1-3 heteroaryl group, meaning that the heteroaryl group contains 1-3 carbon atoms and At least one heteroatom selected from O, S and N. .

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also including, but in no way limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole [1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]Triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole and [1,5-a]pyridyl, etc.

The term "carboxy", either alone or in combination with other terms, such as "carboxyalkyl", means _-CO2H ; the term "carbonyl", either alone or in combination with other terms, such as "aminocarbonyl" or "Acyloxy" means -(C=O).

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino group is independently substituted with one or two alkyl groups, respectively. In some embodiments, alkylamino is a lower alkylamino group with one or two _C1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is a _C1-3 lower alkylamino group. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino, etc.

The term "arylamino" means that an amino group is substituted with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

The term "aminoalkyl" includes a C _1-10 straight or branched chain alkyl group substituted with one or more amino groups. In some embodiments, aminoalkyl is a C _1-6 "lower aminoalkyl" substituted with one or more amino groups, such examples include, but are not limited to, aminomethyl, amino Ethyl, aminopropyl, aminobutyl and aminohexyl.

The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a linear or branched saturated hydrocarbon radical. And the alkylene group can be substituted or unsubstituted, wherein the substituent can be, but not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, Alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy. Such examples include, but are not limited to, methylene ( _-CH2- ), ethylene ( _-CH2 -CH2-), isopropylidene ( _-CH2 - _CH ( _CH3 )-), Ethane-1,1-diyl, 2-methoxypropane-1,1-diyl, 2-hydroxypropane-1,1-diyl, 2-methyl-2-hydroxypropane-1,1- Two bases and so on.

The term "alkenylene" refers to an alkenyl group obtained by removing two hydrogen atoms from a linear or branched alkene. And the alkenylene can be substituted or unsubstituted, wherein the substituent can be, but not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, Alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy. Such examples include, but are not limited to, vinylidene (-CH=CH-), Cl-substituted vinylene (-ClC=CH-), isopropenylene (-C( _CH3 )=CH-), and the like Wait.

The term "alkynylene" refers to an alkynyl group obtained by removing two hydrogen atoms from a straight or branched chain alkyne. And the alkynylene group may be substituted or unsubstituted, wherein the alkynyl group has the meaning of the present invention. Such examples include, but are not limited to, ethynylene (-C≡C-), propargylene ( _-CH2C≡C- ), and the like.

The term "cycloalkylene" refers to a saturated divalent hydrocarbon ring obtained by removing two hydrogen atoms from a monocyclic ring of 3 to 12 carbon atoms or a bicyclic ring of 7 to 12 carbon atoms, wherein carbocyclyl or cycloalkyl Having the meaning as described herein, such examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopent-1-alkenylene, 1-cyclopent- 2-Alkenylene, etc.

The term "heterocyclylene" refers to a monocyclic, bicyclic or tricyclic ring system in which one or more atoms in the ring are independently selected from heteroatoms, and may be fully saturated or contain one or more unsaturations, but not Belongs to the aromatic class, having two points of attachment to the rest of the molecule, where the heterocyclyl group has the meaning as described herein. Such examples include, but are not limited to, piperidine-1,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, aza Cyclobutane-1,3-diyl, pyrrolidine-1,3-diyl, etc.

The term "arylene" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is Aromatic, in which each ring system contains a ring of 3-7 atoms with two points of attachment to the rest of the molecule. The term "arylene" is used interchangeably with the term "arylene ring". where the aryl group has the meaning as defined in the present invention. Examples of arylene groups may include phenylene, naphthylene, and anthracene. The arylene groups can be independently optionally substituted with one or more substituents described herein.

The term "heteroarylene" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic , and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system contains a ring of 5-7 atoms with two points of attachment to the rest of the molecule. wherein the heteroaryl group has the meaning as defined in the present invention. The heteroarylene group is optionally substituted with one or more substituents described herein.

The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), ₁ -pentyloxy (n _- pentyloxy, -OCH2CH2CH2CH2CH3), _{2 -} pentyloxy (-OCH _{( CH3 ) CH2CH2CH3 )} , 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc.

The term "alkylthio" refers to a group in which an oxygen atom in an alkoxy group is replaced by a sulfur atom.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" mean an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, trifluoromethoxy, etc.

The term "hydroxyalkyl" or "hydroxy-substituted alkyl" means that an alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning set forth herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

The term "amino" (alone or in combination with other terms) refers to _-NH2 ;

The term "imino" (alone or in combination with other terms) refers to =NH;

The term "aminoimino" (alone or in combination with other terms) refers to = _NNH2 ;

The term "protecting group" or "PG" refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups. For example, "protecting group for amino" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl. "Carboxyl protecting group" means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

As described in the present invention, -OC(=O)-, -C(=S)-, -OC(=S)-, -N(R ⁷ )C(=S)-, -N(R ⁷ ) There are _two connections in C(=O)-, CH2O, -OS(=O) _t- , -OC(=O)N( ^R7 )- or -C(=O)N( ^R7 )- The point is connected to other groups, as shown in formula (a), it means that both the E and E' ends of -OC(=O)- can be connected to other groups, and in the present invention, the E and E' ends The attached groups are interchangeable.

E-C(=O)O-E' (a).

The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328 -2345.

"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} Sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

As used herein, the term "treating" any disease or disorder, in some of these embodiments, refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder, either physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/ Carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate Sugar, glucuronate, hippurate, hydroiodate/iodide, isethionate, lactate, lacturonate, lauryl sulfate, malate, maleate acid salt, malonate, mandelate, mesylate, methosulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalic acid Salt, Palmitate, Pamoate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Polygalactonate, Propionate, Stearate, Succinate, Sulfosalicylates, Tartrate , tosylate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary, and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by The preparations are carried out by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required. In, for example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use )", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find additional lists of suitable salts.

In addition, the compounds disclosed herein, including their salts, can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization. Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.

Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such ^as2H , ^3H , ^11C , ^13C , ^14C , ^15N , ^17O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes, such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes, such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using eg ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) for substrate tissue distribution measurements, or may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention, using suitable isotopically labeled reagents to replace the previously used unlabeled reagents.

In addition, substitution of heavier isotopes, particularly deuterium (ie, ² H or D), may provide certain therapeutic advantages that result from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compounds of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, _D2O , acetone _- d6, _DMSO -d6.

In another aspect, the present invention relates to intermediates for the preparation of compounds encompassed by formula (I).

In another aspect, the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. In some embodiments, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.

"Combination" means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the disclosed compound and the combination partner may be administered independently at the same time or may be administered separately at intervals, particularly It is to cause the joint partners to exhibit cooperation, eg synergy. As used herein, the terms "co-administration" or "co-administration" and the like are intended to encompass the administration of a selected combination partner to a single individual (eg, a patient) in need thereof, and are intended to include where the substances are not necessarily administered by the same route of administration or at the same time treatment plan. The term "pharmaceutical combination" as used herein means a product resulting from mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the disclosed compound and the combination partner, are administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredients, such as the disclosed compounds and the combination partner, are administered to a patient simultaneously, jointly or sequentially without a specific time limit as separate entities, wherein the administration provides therapeutically effective levels of both compounds in the patient. . The latter also applies to cocktail therapy, eg the administration of 3 or more active ingredients.

It should be noted that the term "inhibiting HCV viral protein" in the present invention should be understood in a broad sense, which includes not only inhibiting the expression level of HCV viral protein, but also inhibiting the activity level of HCV viral protein, and the level of virus assembly and release. Wherein, the HCV protein expression level includes, but is not limited to, the translation level of the viral protein gene, the post-translational modification level of the protein, the replication level of the genetic material of the progeny, and the like.

Description of Compounds of the Invention

The invention relates to a macrocyclic compound and a pharmaceutical preparation thereof, which can effectively inhibit HCV infection, especially the activity of HCV NS3/4A protein.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, enantiomer of the compound represented by formula (I) Forms, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs:

wherein: Ring A and Ring B are each independently a cycloalkyl, heterocyclyl, aryl or heteroaryl group;

Each R ¹ and R ² is independently H, deuterium, hydroxyl, F, Cl, Br, I, N ₃ , -SR ⁵ , -S(=O)R ⁵ , -S(=O) ₂ R ⁵ , - C(=O)OR ⁵ , -C(=O)R ⁵ , -N(R ⁷ )S(=O) ₂ R ⁵ , -N(R ⁷ )S(=O) ₂ NR ⁷ R ¹¹ , - S(=O) ₂ NR ⁷ R ¹¹ , -C(=O)NR ⁷ R ¹¹ , -N(R ⁷ )C(=O)R ⁵ , cyano, nitro, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, alkylthio, cycloalkyl, cycloalkyl-O-, heterocyclyl, aryl or heteroaryl;

^R3 and ^R4 are each independently H, deuterium, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl cycloalkyl, aryl or heteroaryl;

L is -C(=O)-, -OC(=O)-, -C(=S)-, -OC(=S)-, -N(R ⁷ )C(=S)- or -N( R ⁷ )C(=O)-;

表示-X或＝X；当

为-X时，X为CR⁵R⁶、NR⁷、O或S；当

为＝X时，X为CR⁵或N；

means -X or =X; when

When -X, X is CR ⁵ R ⁶ , NR ⁷ , O or S; when

When =X, X is CR ⁵ or N;

Y is -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S- or -S(=O) _t -;

T is -CR ⁵ R ⁶ -, -O-, -S-, -NR ⁷ -, -CH ₂ O-, -OS(=O) _t -, -OC(=O)-, -OC(=O )N(R ⁷ )- or -N(R ⁷ )C(=O)-;

W is CR ⁵ or N;

Q is -(CR ⁵ R ⁶ ) _p -Z-(CR ⁸ R ⁹ ) _q -;

Z is a bond, -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S-, -S(=O) _t -, -C(=O)-, -OC(=O)-, -OC(=O)N(R ⁷ )-, -N(R ⁷ )C(=O)-, -C(=O)N(R ⁷ )-, alkenylene, alkynylene, cycloalkane radical, heterocyclylene, arylene, heterocyclylene-O, arylene-O, arylene-S, arylene-N, or heteroarylene;

Each ^R5 , R6, ^R8 and ^R9 is independently H, deuterium, hydroxy, amino, F, ^Cl , Br, I, alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl or Heteroaryl;

Each ^R7 and ^R11 is independently H, deuterium, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

m and n are each independently 0, 1, 2, 3 or 4;

each t is independently 1 or 2;

p and q are each independently 0, 1, 2, 3, 4 or 5;

表示

或

express

or

The above-mentioned alkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyl-O-, haloalkyl, haloalkoxy, heterocyclyl, aryl , heteroaryl, alkenylene, cycloalkylene, heterocyclylene, heterocyclylene alkyl, arylene, heterocyclylene-O, heteroarylene-O, arylene-S, Arylene-N and heteroarylene are independently optionally replaced by 1, 2, 3 or 4 selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, alkyl, alkenyl , alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents.

In some embodiments, wherein Ring A and Ring B are each independently a _C3-10 cycloalkyl, _C2-10 heterocyclyl, _C6-10 aryl, or _C1-9 heteroaryl group;

Each R ¹ and R ² is independently H, deuterium, hydroxy, F, Cl, Br, I, N ₃ , amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyl -O-, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

为＝X时，X为CR⁵或N；

When =X, X is CR ⁵ or N;

Y is -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S- or -S(=O) _t -;

Each R ⁵ and R ⁶ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, or C _{2- 6} alkynyl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

m and n are each independently 0, 1, 2, 3 or 4;

The above-mentioned C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-10 cycloalkyl, C _{1 -6} haloalkyl, C _1-6 haloalkoxy, C _2-10 heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl independently optionally selected from 1, 2, 3 or 4 Deuterium, hydroxyl, F, Cl, Br, I, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C Substituents of _1-6 alkylamino, C _3-10 cycloalkyl, C _6-10 aryl, C _1-9 heteroaryl or C _2-10 heterocyclyl.

In other embodiments, wherein Ring A and Ring B are each independently phenyl, pyridyl, thiazolyl, oxazolyl, imidazolyl, furyl, thienyl, pyrazolyl, isoxazolyl, pyrrole group, quinolinyl, indolyl or naphthyl group.

In some embodiments, wherein L is -C(=O)-, -OC(=O)- or -NHC(=O)-;

R ⁴ is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl C _1-6 alkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl, C _{2- 10} heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano , nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _{1 -6} alkylamino, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl substituent.

^In some embodiments, wherein Q is ^- ( ^CR5R6 ) _p -Z-( ^CR8R9 ) _q- ;

Z is a bond, -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S-, -S(=O) ₂ -, C _2-6 alkenylene, C _2-6 alkynylene, C _3-10 cycloalkylene, C _2-10 heterocyclylene, C _6-10 arylene, C _6-10 arylene-O, C _6-10 arylene-S, C _6-10 Arylene-N or C _1-9 heteroarylene;

Each of R ⁵ , R ⁶ , R ⁸ and R ⁹ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane oxy, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

p and q are each independently 0, 1, 2, 3, 4 or 5.

In some embodiments, wherein R ³ is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkane base C _1-6 alkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl, C _1-6 alkyl, C _{2- 10} heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano , nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _{1 -6} alkylamino, C _3-6 cycloalkyl, C _2-6 heterocycloalkyl, C _6-10 aryl or C _1-9 heteroaryl substituent.

为In some embodiments, wherein

for

each of A ¹ and A ² is independently CR ¹⁰ or N;

A ³ is CR ⁵ R ⁶ , NR ⁷ , O or S;

Each R ¹ and R ² is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, N ₃ , cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyl -O-, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁵ and R ⁶ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

Each R ¹⁰ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy group, C _2-6 alkenyl or C _2-6 alkynyl;

wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _{1-6 6} haloalkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkane-O, C _2-10 heterocyclyl, C _6-10 aryl and C _1-9 heteroaryl independently optionally by 1 , 2, 3 or 4 are selected from deuterium, hydroxyl, F, Cl, Br, I, amino, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-6 cycloalkyl, C _2-6 heterocyclyl, C _6-10 Substituents of aryl or C _1-9 heteroaryl.

为In other embodiments, wherein

for

In some embodiments, it has a structure as shown in formula (I'),

Or stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable compounds of the compound represented by formula (I') salt or prodrug;

为in,

for

each of A ¹ and A ² is independently CR ¹⁰ or N;

A ³ is CR ⁵ R ⁶ , NR ⁷ , O or S;

Each R ¹ and R ² is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, N ₃ , cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl -O, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁵ and R ⁶ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _{2- 6} alkynyl, C _6-10 aryl or C _1-9 heteroaryl;

Each R ⁷ is independently H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl, or C _{1- 9} heteroaryl;

Each R ¹⁰ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy group, C _2-6 alkenyl or C _2-6 alkynyl;

wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkyl, C _{1-6 6} haloalkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkyl, C _1-6 alkyl, C _2-10 heterocyclyl, C _3-8 cycloalkane-O, C _6-10 aryl and C _1-9 heteroaryl independently optionally by 1, 2, 3 or 4 selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylamino, C _3-6 cycloalkane substituted with substituents of C 2-6 heterocyclyl or C _2-6 heterocyclyl.

In other embodiments, wherein each A ¹ and A ² is independently CR ¹⁰ or N;

A ³ is NH, O or S;

Each ^R10 is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, ethynyl, trifluoromethyl or trifluoro methoxy;

Each R1 and ^R2 is independently H, deuterium, hydroxy, F, Cl, Br, ^I , amino, cyano, nitro, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclo Amyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyclopropyloxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazole radical, furyl, imidazolyl, thienyl, pyrazolyl, isoxazolyl, indolyl, naphthyl, ethynyl, vinyl, propynyl or propenyl;

The above-mentioned methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, cyclopropyloxy, trifluoro Methyl, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, pyrazolyl, isoxazolyl, indolyl, naphthyl, ethynyl, vinyl, Propynyl and propenyl are independently optionally replaced by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, methyl, ethyl, isopropyl, butyl, tert-butyl, Substituents of methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, trifluoromethyl or trifluoromethoxy.

为In other embodiments, wherein,

for

In other embodiments, wherein R ³ and R ⁴ are each independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _2-10 heterocyclyl, C _6-10 aryl or C _1-9 heteroaryl;

wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _2-10 heterocyclyl, C _{6 -10} aryl and C _1-9 heteroaryl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, cyano, nitro, C _{1- 4} alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylamino, C _{3 -6} cycloalkyl, _C2-6 heterocyclyl, _C6-10 aryl or _C1-9 heteroaryl substituent.

^In other embodiments, wherein ^R3 and R4 are each independently H, deuterium, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, morpholinyl, piperazinyl, pyrazinyl, piperidinyl, phenyl, propenyl, propynyl, oxazole radical, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, furanyl, thienyl or pyridyl;

The methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, Cyclohexenyl, morpholinyl, piperazinyl, pyrazinyl, piperidinyl, phenyl, propenyl, propynyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl , thiazolyl, triazolyl, furanyl, thienyl, and pyridyl are independently optionally substituted by 1, 2, 3 or 4 groups selected from deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl , isopropyl, butyl, tert-butyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, trifluoromethyl or trifluoromethoxy substituent.

In other embodiments, wherein T is -O-, -S- or ^-NR7- ;

^R7 is H, deuterium, F, Cl, Br, I, methyl, ethyl, isopropyl or trifluoromethyl.

In other embodiments, wherein W is CH or N.

^In other embodiments, wherein Q is ^- ( ^CR5R6 ) _p -Z-( ^CR8R9 ) _q- ;

Z is a bond, -CR ⁵ R ⁶ -, -NR ⁷ -, -O-, -S-, -S(=O) ₂ -, C _2-6 alkenylene, C _2-6 alkynylene, C _3-8 cycloalkylene, C _2-10 heterocyclylene, C _6-10 arylene, C _6-10 arylene-O or C _1-9 heteroarylene;

Each R ⁵ , R ⁶ , R ⁸ and R ⁹ is independently H, deuterium, hydroxy, F, Cl, Br, I, amino, C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkyne base;

R ⁷ is H, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl or C _6-10 aryl;

p and q are each independently 0, 1, 2, 3, 4 or 5;

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, C _2-10 heterocyclyl, C _{6 -10} aryl, C _2-6 alkenylene, C _2-6 alkynylene, C _3-8 cycloalkylene, C _2-10 heterocyclylene, C _6-10 arylene, C _{6- 10} Arylene-O and C _1-9 Heteroarylene independently optionally by 1, 2, 3 or 4 selected from H, deuterium, hydroxyl, F, Cl, Br, I, amino, cyano, nitro base, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 Substituents of alkylamino, C _3-6 cycloalkyl or C _2-6 heterocyclyl.

In other embodiments, Z is a bond, _-CH2- , ^-NR7- , -O-, -S-, -S(=O) _2- , vinylene, ethynylene, cyclopropylene , cyclobutylene, cyclopentylene, cyclohexylene, phenylene-O, phenylene-S, thiazolylidene, imidazolylidene, or phenylene;

Each of ^R5 , R6, ^R8 and ^R9 is independently H, deuterium, hydroxy, F, ^Cl , Br, I, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl , vinyl or ethynyl;

R ⁷ is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

The methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinylidene, Ethynyl, cyclopropylidene, cyclobutylene, cyclopentylene, cyclohexylene, phenylene-S, thiazolylylene, imidazolylide, phenylene-O, or phenylene can be independently optionally Substituted with 1, 2, 3 or 4 substituents selected from H, deuterium, F, Cl, Br, I, amino, methyl, methoxy, hydroxy, nitro, cyano.

为In other embodiments, wherein,

for

Each R1 and R2 is independently H, deuterium, hydroxy, F, Cl, Br, ^I , amino, cyano, nitro, methyl, ethyl, isopropyl, butyl, tert ^- butyl, cyclopropyl base, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxa azolyl, furanyl, imidazolyl, thienyl, indolyl, naphthyl, ethynyl, vinyl, propynyl or propenyl;

n is 0, 1, 2, 3 or 4;

The above-mentioned methyl, ethyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, tri Fluoromethyl, trifluoromethoxy, phenyl, pyridyl, pyrrolyl, thiazolyl, oxazolyl, furyl, imidazolyl, thienyl, indolyl, naphthyl, ethynyl, vinyl, propyne and propenyl are independently optionally replaced by 1, 2, 3 or 4 groups selected from H, deuterium, hydroxy, F, Cl, Br, I, amino, methyl, ethyl, isopropyl, methoxy, ethylene group, ethynyl, trifluoromethyl or trifluoromethoxy substituent.

In some embodiments, it has one of the following structures:

或它们的立体异构体、几何异构体、互变异构体、对映异构体、氮氧化物、水合物、溶剂化物、代谢产物以及药学上可接受的盐或前药。

Or their stereoisomers, geometric isomers, tautomers, enantiomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs.

The compound of the present invention (herein, the expression "the compound represented by formula (I) or the stereoisomer, geometric isomer, tautomer, enantiomer of the compound represented by formula (I)" compounds, nitrogen oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts or prodrugs"), can be used in the manufacture of medicinal products for the treatment of acute and chronic HCV infections, including those described herein. Further, the compounds of the present invention can be used to produce anti-HCV preparations. Thus, the compounds of the present invention can be used to produce a medicinal product for alleviating, preventing, controlling or treating HCV-mediated diseases, especially HCV NS3/4A protein-mediated diseases. Thus, the compound of the present invention can be used as an active ingredient in a pharmaceutical composition, which can include a compound represented by formula (I), and can further include at least one pharmaceutically acceptable carrier, adjuvant or dilution agent.

Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" means that the substance or composition employed must be chemically or toxicologically compatible with the other components of the formulation and the mammal for which it is to be treated. Those skilled in the art can specifically select a "pharmaceutically acceptable" substance or composition depending on the other components employed and the subject being treated, eg, humans.

The salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or salts of separated enantiomers of the compounds of formula (I), but are not necessarily pharmaceutically acceptable Salt.

If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, eg, using inorganic or organic acids. Among them, examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids include, but are not limited to, acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, and salicylic acid; pyranonic acids such as glucuronic acid and Galacturonic acid; alpha-hydroxy acids, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; sulfonic acids, such as p-toluenesulfonic acid, ethanesulfonic acid acid and so on.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, eg, using inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali metal hydroxides or alkaline earths Metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compositions, Formulations and Administration of Compounds of the Invention

The pharmaceutical composition comprises any one of the compounds of the present invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. The pharmaceutical composition can be used for treating hepatitis C virus (HCV) infection or hepatitis C disease, and in particular, it has a good inhibitory effect on HCV NS3/4A protein.

The pharmaceutical composition further comprises an anti-HCV drug. The anti-HCV drug may be any known anti-HCV drug other than the compound of the present invention. For example, interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the generation of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'- Monophosphate dehydrogenase inhibitors, amantadine, rimantadine, ritonavir, bavituximab, Civacir ^™ , boceprevir, telaprevir, Sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI -207127), dasabuvir(ABT-333), beclabuvir(BMS-791325), elbasvir(MK-8742), ombitasvir(ABT-267), neceprevir(ACH-2684), tegobuvir(GS-9190), grazoprevir(MK- 5172), sovaprevir (ACH-1625), samatasvir (IDX-719), setrobuvir, veruprevir (ABT-450), erlotinib (erlotinib), simeprevir (TMC-435), asunaprevir (BMS-650032), vaniprevir ( MK-7009), faldaprevir(BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530, ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir(GS-9451) , BZF-961, GS-9256, ANA975, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX -813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479 , UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-072, PF-00868554, BI-207127, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055, or a combination thereof. Wherein, the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, compound α-interferon, interferon γ or its combination. The pharmaceutical composition further comprises at least one HCV inhibitor, which is used to inhibit at least one of HCV replication process and HCV viral protein function, wherein the HCV replication process is selected from HCV entry, uncoating , the complete viral cycle of HCV translated, replicated, assembled and released; the HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point required for HCV viral replication (IRES) and inosine monophosphate dehydrogenase (IMPDH).

When useful in therapy, a therapeutically effective amount of a compound of the present invention, especially a compound of formula (I) and pharmaceutically acceptable salts thereof, can be administered as a raw chemical and can also be provided as an active ingredient of a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable salts thereof carrier, diluent or excipient. As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to demonstrate a meaningful patient benefit (eg, reduction in viral load). When a single active ingredient is used for administration alone, the term refers to that ingredient only. When used in combination, the term refers to the combined amounts of active ingredients that, whether administered in combination, sequentially or simultaneously, result in a therapeutic effect. The compounds of the present invention, especially the compounds of formula (I) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to its recipient. According to another aspect of the content of the present invention, there is also provided a method for the preparation of a pharmaceutical formulation, the method comprising combining a compound of the present invention, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable salts. An acceptable carrier, diluent or excipient is mixed. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation , allergic reactions or other problems and complications commensurate with a reasonable benefit/risk ratio and are effective for the intended use.

Pharmaceutical formulations may be presented in unit dosage form, each unit dosage containing a predetermined quantity of active ingredient. Dosage levels of the compounds of the present invention are between about 0.01 milligrams per kilogram (mg/kg) body weight/day and about 250 mg/kg body weight/day, preferably between about 0.05 mg/kg body weight/day and about 100 mg/kg body weight /day, often as a monotherapy for the prevention or treatment of HCV-mediated disease. The pharmaceutical compositions of the present invention may generally be administered from about 1 to about 5 times per day or as a continuous infusion. Such dosing can be used as long-term or short-term therapy. The amount of active ingredient to be mixed with the carrier material to prepare a single dosage form will depend on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, weight and condition of the patient and change. Preferred unit dosage forms are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of the active ingredient herein above. Treatment can be initiated with small doses that are clearly below the optimal dose of the compound. Thereafter, increase the dose in smaller increments until the best effect under the circumstances is achieved. In general, the compound is optimally administered at a concentration level that generally provides effective antiviral results without causing any deleterious or toxic side effects.

When a composition of the present invention comprises a compound of the present invention in combination with one or more other therapeutic or prophylactic drugs, the dosage levels of the compound and the additional drug are typically in a monotherapy regimen, 5% of the normally administered dose About 10-150%, more preferably about 10-80% of the normally administered dose. The pharmaceutical formulations are suitable for administration by any suitable route, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal) , intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) routes. Such formulations may be prepared by any method known in the art of pharmacy, for example by admixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.

Pharmaceutical formulations suitable for oral administration are presented in discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foam formulations or effervescent formulations (whips). ); or an oil-in-water emulsion or a water-in-oil emulsion.

For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutically acceptable carrier such as an edible sugar such as starch or mannitol. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules are prepared by preparing a powdered mixture as described above and filling formed gelatin shells. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycols can be added to the powdered mixture prior to the filling operation. Disintegrating or solubilizing agents (eg, agar, calcium carbonate, or sodium carbonate) that will improve the availability of the drug when the capsule is taken can also be added.

Furthermore, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth or sodium alginate), carboxymethyl cellulose , polyethylene glycol, etc. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For example, a tablet may be made by forming a powder mixture, granulating or pre-tabletting, adding a lubricant and a disintegrant, and compressing into a tablet. The suitably comminuted compound is combined with a diluent or base as described above, optionally with a binder (eg carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (eg paraffin), An absorption accelerator (quaternary salt) and/or an absorbent (eg bentonite, kaolin or dicalcium phosphate) are mixed to prepare a powdered mixture. The powdered mixture may be granulated by wetting with a binder (eg, syrup, starch slurry, acadiamucilage, or solutions of cellulosic or polymeric materials) and pressing through a sieve. As an alternative to granulation, the powdered mixture can be passed through a tablet machine, resulting in poorly formed agglomerates being recrushed into granules. The granules can be lubricated to prevent sticking to the dies of the tablet press by adding stearic acid, stearate salts, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets without going through a granulation or pre-tabletting step. Transparent or opaque protective coatings consisting of a seal coat of shellac, a coating of sugar or polymeric material and a polish coating of wax may be provided. Dyestuffs can be added to these coatings to distinguish different unit doses.

Oral liquid preparations such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs can be prepared by using a non-toxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers), preservatives, flavor additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) may also be added Wait.

Dosage unit formulations for oral administration can be microencapsulated, if appropriate. The formulations can also be formulated for delayed or sustained release, for example, by coating or entrapping in particulate materials such as polymers, waxes, and the like.

The compounds of the present invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, can also be administered in liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be composed of a variety of phospholipids such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the present invention, especially the compounds of formula (I) and pharmaceutically acceptable salts thereof, can also be delivered by using monoclonal antibodies as individual carriers to which the compound molecules are coupled. Compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. In addition, compounds can be coupled with a class of biodegradable polymers for controlled release of drugs such as polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, poly Cross-linked copolymers or amphiphilic block copolymers of acetals, polydihydropyrans, polycyanoacrylates and hydrogels.

Pharmaceutical formulations suitable for transdermal administration are available as discrete patches to maintain intimate contact with the epidermis of the recipient for extended periods of time. For example, the active ingredient may be delivered via an iontophoresis patch, see generally Pharmaceutical Research 1986, 3(6), 318.

Pharmaceutical formulations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches .

Pharmaceutical formulations suitable for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations suitable for nasal administration (wherein the carrier is a solid) include coarse powders having a particle size in the range of, for example, 20-500 microns, by snorting, that is, through the nasal passages, rapidly from a coarse powder container near the nose. inhaled. Suitable formulations for administration as a nasal spray or nose drops, wherein the carrier is a liquid, include aqueous or oily solutions of the active ingredient.

Pharmaceutical formulations suitable for administration by inhalation include fine particle dusts or mists, and aerosol sprays can be delivered by different types of metered dose compressed aerosols, nebulizers, insufflators or otherwise. prepared in the device.

Pharmaceutical formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, creams, gels, pastes, foams or sprays.

Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions and aqueous and non-aqueous sterile suspensions. Aqueous and non-aqueous sterile injectable solutions may contain antioxidants, buffers, bacteriostatic agents. Aqueous and non-aqueous sterile suspensions may include suspending and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, such as sealed Ankai and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, eg, water for injection, just before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

It will be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other ingredients commonly used in the art in connection with the type of formulation in question, for example, such formulations suitable for oral administration may include flavoring agents.

Use of the Compounds and Pharmaceutical Compositions of the Invention

The present invention provides the use of the compound or the pharmaceutical composition of the present invention in preparing a medicine, which can be used for at least one of inhibiting the HCV replication process and inhibiting the HCV viral protein function. The HCV replication process is selected from the complete viral cycle of HCV entry, uncoating, translation, replication, assembly or release of HCV. The HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV virus replication. Any compound or pharmaceutical composition of the present invention can be used for treating hepatitis C virus (HCV) infection or hepatitis C disease, and in particular, it has a good inhibitory effect on HCV NS3/4A protein.

The treatment method comprising the administration of the compound of the present invention or the pharmaceutical composition further comprises administering other HCV drugs to the patient, whereby the compound of the present invention can be combined with other anti-HCV drugs, wherein the anti-HCV drug For interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the generation of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate depletion Hydrogenase inhibitors, amantadine, rimantadine, ritonavir, Bavituximab, Civacir ^™ , boceprevir, telaprevir, sofosbuvir (sofosbuvir), ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127) , dasabuvir(ABT-333), beclabuvir(BMS-791325), elbasvir(MK-8742), ombitasvir(ABT-267), neceprevir(ACH-2684), tegobuvir(GS-9190), grazoprevir(MK-5172), sovaprevir(ACH-1625), samatasvir(IDX-719), setrobuvir, veruprevir(ABT-450), erlotinib, simeprevir(TMC-435), asunaprevir(BMS-650032), vaniprevir(MK-7009) ), faldaprevir(BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530, ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir(GS-9451), BZF- 961, GS-9256, ANA975, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX- 081 89, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-072, PF-00868554, BI-207127, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055, or a combination thereof. Wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, compound alpha-interferon, interferon gamma or its combination.

And the treatment method comprising the administration of the compound of the present invention or the pharmaceutical composition further comprises the administration of other anti-HCV drugs, wherein other anti-HCV drugs can be administered in combination with the compound of the present invention or its pharmaceutical composition, the compound of the present invention or the drug The composition is presented as a single dosage form, or separate compounds or pharmaceutical compositions are presented as part of a multiple dosage form. Other anti-HCV drugs may or may not be administered concurrently with the compounds of the present invention. In the latter case, the administration may be staggered, eg, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an amount effective to treat or lessen the severity of one or more of the disorders referred to herein. According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or reducing the severity of the disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.

General synthetic procedure

In general, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I). The following reaction schemes and examples serve to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Reagent Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate and used.

The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectra were performed with CDC13, _{DMSO -} d6, _CD3OD , or acetone _- d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, two doublets), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315B DAD detector for analysis , ESI source applied to LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315D DAD detector were used for analysis, ESI sources are used in LC-MS spectrometers.

Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were read by recording UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1:

Table 1

time (min) A (CH₃CN, 0.1% HCOOH) B (H₂O, 0.1% HCOOH) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

Compound purification was assessed by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, 2.1 x 30 mm, 4 μm, 10 min, flow rate 0.6 mL/min , 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was kept at 40°C.

The following abbreviations are used throughout this disclosure:

AcOH acetic acid

BBr ₃ Boron tribromide

BSA bovine serum albumin

Br ₂ Bromine

Bn benzyl

BOC, Boc tert-butoxycarbonyl

BAST bis(2-methoxyethyl)aminosulfur trifluoride

Cs ₂ CO ₃ Cesium Carbonate

CHCl ₃ chloroform

CDC1 ₃ deuterochloroform

CD ₃ OD Deuterated methanol

Cu copper

CuI cuprous iodide

CH ₂ Cl ₂ , DCM Dichloromethane

CDI N,N'-Carbonyldiimidazole

CBZ, Cbz benzyloxycarbonyl

DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene

DBAD Di-tert-butyl azodicarboxylate

DCE 1,2-Dichloroethane

DMF N,N-Dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO Dimethyl sulfoxide

DMSO-d ₆ -deuterated dimethyl sulfoxide

Dppa Diphenyl Phosphate Azide

DIPEA Diisopropylethylamine

DME Glycol Dimethyl Ether

DAST diethylaminosulfur trifluoride

DPPPy Diphenyl-2-pyridylphosphine

Dess-Martin (1,1,1-triacetoxy)-1,1-dihydro-1,2-beniodon-3(1H)-one

EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc Ethyl acetate

EA Ethyl acetate

Et ₂ O ether

Et ₂ NSF ₃ Diethylamine Sulfur Trifluoride

Et ₃ N,TEA Triethylamine

Fe iron

Fmoc 9-Fluorenemethyleneoxycarbonyl

HCl.EA Hydrogen chloride Ethyl acetate

HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

HBr Hydrobromic acid

HCl hydrochloric acid

HOAt, HOAT 1-Hydroxy-7-azabenzotriazole

HOBT 1-Hydroxybenzotriazole

_H2Hydrogen

H ₂ O ₂ hydrogen peroxide

H ₂ O water

HOAc acetic acid

I ₂ iodine

IPA isopropyl alcohol

IMPDH inosine monophosphate dehydrogenase

IRES internal ribosome entry point

K ₂ CO ₃ Potassium Carbonate

KOH Potassium Hydroxide

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide

LiN(SiMe ₃ ) ₂ bis(trimethylsilyl) lithium amide

Lawesson's Reagent 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-phosphoran-2,4-disulfide

MTBE methyl tert-butyl ether

MCPBA meta-chloroperoxybenzoic acid

MgSO ₄ Magnesium Sulfate

MeOH, CH ₃ OH methanol

MeI iodomethane

MeCN, CH ₃ CN Acetonitrile

mL milliliter

NH ₃ ammonia

NH ₄ C1 Ammonia Chloride

NMP N-methylpyrrolidone

NIS N-Iodosuccinimide

_N2 nitrogen

NaHCO ₃ Sodium Bicarbonate

NaBH ₄ sodium borohydride

NaBH ₃ CN Sodium cyanoborohydride

NaOtBu sodium tert-butoxide

NaOH sodium hydroxide

NaClO ₂ Sodium Chlorite

NaCl Sodium Chloride

NaH ₂ PO ₄ Monosodium Phosphate

NaH sodium hydride

NaI sodium iodide

Na ₂ SO ₄ Sodium Sulfate

NBS N-bromosuccinimide

PPh ₃ MeBr Bromomethyltriphenylphosphine

P(t-bu) ₃ tris(tert-butyl)phosphine

Pd/C Palladium/Carbon

PE petroleum ether (60–90℃)

PBS Phosphate Buffered Saline

POC1 ₃ Phosphorus oxychloride

PPA polyphosphoric acid

Pd(PPh ₃ ) ₄ tetrakistriphenylphosphonium palladium

Pd(dppf)Cl ₂ 1,1'-bis(diphenylphosphorus)ferrocene]palladium dichloride

PhNTf ₂ N-phenylbis(trifluoromethanesulfonyl)imide

P-TSA/PTSA p-toluenesulfonic acid

PMB p-methoxybenzyl

RT rt room temperature

rf reflow

Rt retention time

SEMCl 2-(trimethylsilyl)ethoxymethyl chloride

SbCl ₃ Antimony Trichloride

SmCl ₃ Samarium Chloride

TBME methyl tert-butyl ether

TBTU O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate

THF tetrahydrofuran

TFA trifluoroacetic acid

TBAI Tetrabutylammonium iodide

TBS tert-butyldimethylsilyl

TBDPS tert-butyldiphenylsilyl

TEAF triethylamine carboxylic acid

Tf ₂ O trifluoromethanesulfonic anhydride

TFAA trifluoroacetic anhydride

TsOH p-toluenesulfonic acid

TMSA Trimethylsilylacetylene

TMSCl Trimethylchlorosilane

TBDMSOTf tert-butyldimethyl-p-toluenesulfonic acid silane

TCCA trichloroisocyanuric acid

t-BuOK Potassium tert-butoxide

TEMPO 2,2,6,6-Tetramethylpiperidine-nitrogen-oxide

TEBAC Benzyltriethylammonium chloride

Mylardaic acid 2,2-dimethyl-1,3-dioxane-4,6-dione

resolve resolution

Synthetic method 1

Compound 5 can be prepared by synthetic method 1, wherein R ¹ , R ² , A ¹ , A ² , m, and n have the meanings described in the present invention, and compound 3 is synthesized from compound 1 and compound 2 under the action of a base, The bases used are sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. Compound 3 is synthesized in the acetic acid system under the action of reduced iron powder to obtain compound 4, and compound 4 is further under the action of POCl ₃ and catalyst N,N-dimethylaniline to form compound 5.

Synthetic method 2

Compound 9 can be prepared by synthetic method 2, wherein R ³ has the meaning described in the present invention. First, compound 6 and compound 7 obtain compound 8 under the action of CDI and DBU, and then compound 8 is further deprotected and formed into a salt to obtain compound 9. .

Synthetic method 3

Compound 18 can be prepared by synthetic method 3, wherein X ¹ is OH, Cl, etc.; R ¹ , R ² , R ³ , A ¹ , A ² , Q, R ⁴ , L, m, n have the Meaning; the protecting group Pg is Boc, Fmoc, Cbz, Bn, PMB, etc., and the bases used are sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, and the like. Compound 5 and compound 10 form compound 11 under basic conditions, and compound 11 further forms compound 12 with compound 9 under the action of a condensing agent. Compound 12 is deprotected to form compound 13, and compound 13 and compound 14 form compound 15 again under the action of a condensing agent. Compound 15 forms compound 16 under the action of catalysts (such as Grubbs second-generation catalyst, Jan's 1B catalyst, Jan's 1C catalyst, etc.), and finally compound 16 is further deprotected to form compound 17, and compound 17 reacts with compound 17' to obtain compound 18.

Synthetic method 4

Compound 18 can be prepared by synthetic method 4, wherein X ¹ is OH, Cl, etc.; R ¹ , R ² , R ³ , A ¹ , A ² , Q, R ⁴ , L, m, n have the Meaning; the protecting group Pg is Boc, Fmoc, Cbz, Bn, PMB, etc., and the bases used are sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, and the like. Wherein, compound 20 can be synthesized by reacting compound 10 with compound 19, then removing the amino protecting group to obtain compound 21, and then reacting compound 21 with compound 14 to obtain compound 22. Compound 22 can obtain compound 23 under the action of a catalyst, compound 23 can be reacted with compound 5 under basic conditions to obtain compound 24, and compound 24 can be hydrolyzed to obtain compound 25. And compound 26 can be synthesized by compound 25 and compound 7 under the action of CDI, compound 27 can be obtained after the deprotection of compound 26, and compound 18 can be obtained by reaction of compound 27 and compound 17'.

Synthetic method 5

Compound 18 can be prepared by synthetic method 5, wherein X ¹ is OH, Cl, etc.; R ¹ , R ² , R ³ , A ¹ , A ² , Q, R ⁴ , L, m, n have the Meaning; the protecting group Pg is Boc, Fmoc, Cbz, Bn, PMB, etc., the protecting group Pg2 is TBS, TES, TBDPS, PMB, etc., the base used is sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide , Sodium tert-butoxide, etc. Compound 10 is reacted with compound 9 to obtain compound 28, and then the amino protecting group is removed to obtain compound 29, and then compound 29 is reacted with compound 14 to obtain compound 30. The hydroxyl group in compound 30 is protected to obtain compound 31, and then compound 31 is obtained under the action of a catalyst (Grubbs second-generation catalyst, Jan's 1B catalyst, Jan's 1C catalyst, etc.) to obtain compound 32, and compound 32 removes the hydroxyl protecting group Compound 33 was obtained, followed by compound 5 under basic conditions to obtain compound 26. Compound 26 is further removed from the amino protecting group to obtain compound 27, and compound 27 reacts with compound 17' to obtain compound 18.

Example

Example 1

synthetic route

Step 1: Synthesis of Compounds 1-3

Benzaldehyde (95.6 mL, 943 mmol), glycine ethyl ester hydrochloride (131 g, 943 mmol) and Na ₂ SO ₄ (80 g, 565 mmol) were added to 900 mL of TBME, then cooled to 0 °C and triethylamine ( 197 mL, 1414 mmol), after the addition was complete, the reaction mixture was warmed to 25°C and stirred at this temperature for 24 hours. The mixture was filtered with celite to remove solids, the filtrate was concentrated under reduced pressure, and the obtained crude product was dried under vacuum to give compound 1-3 (180 g, yield: 100%) as a pale yellow oil, which was used directly without further purification. Proceed to the next reaction.

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.28 (s, 1H), 7.86-7.71 (m, 2H), 7.50-7.32 (m, 3H), 4.47-4.32 (m, 2H), 4.29-4.18 ( m, 2H), 1.32–1.22 (m, 3H) ppm.

Step 2: Synthesis of Compounds 1-4

Lithium tert-butoxide (17.60 g, 220 mmol) was added to 250 mL of toluene, and then a solution of compound 1-3 (22.00 g, 117 mmol) in toluene (50 mL) and trans-1 were added dropwise at 0 °C. A solution of 4-dibromo-2-butene (20.00 g, 94 mmol) in toluene (50 mL), and maintaining the same rate of addition of the two solutions, was added dropwise in about 1 hour. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for two hours, quenched with 200 mL of water, back extracted twice with 200 mL of TBME, and the organic phases combined. Then add 200 ml of 1N hydrochloric acid solution to the above-mentioned combined organic phases, stir for two hours, separate, extract the obtained organic phase with 150 ml of water once, then add sodium chloride (131.00 g, 2241 mmol) to the combined aqueous phase and 200 mL of TBME, and the resulting mixture was adjusted to pH between 12-13 with 10N aqueous NaOH. The organic phase was separated, the aqueous phase was extracted with 100 mL of TBME, the organic phases were combined, Boc ₂ O (21 mL, 98 mmol) was added to the combined organic phases, the resulting reaction solution was stirred at room temperature overnight, and then heated to 60° C. and continued to stir for two hours. Hour. After that, it was cooled to room temperature, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a yellow oily substance 1-4 (12 g, yield 50%).

¹ H NMR (400MHz, CDCl ₃ ): δ5.17-5.80(m,1H), 5.29(s,1H), 5.06-5.09(m,1H), 4.12-4.19(m,2H), 2.17-2.14( m, 1H), 1.77 (s, 1H), 1.43 (s, 1H), 1.41 (s, 9H), 1.24 (t, J=7.2 Hz, 3H) ppm.

Step 3: Synthesis of Compounds 1-5

Add Alcalase 2.4L (52mL) proteolytic enzyme to sodium phosphate buffer solution (0.1N, 550mL, pH=8), then warm up to 39°C, add 50% aqueous sodium hydroxide solution to adjust the pH of the solution to 8.0 . At this temperature, a solution of compound 1-4 (10.58 g, 42.5 mmol) in DMSO (100 mL) was added slowly over 20 minutes. Then, the reaction mixture was heated to 40° C. and stirred for 24 hours. During the reaction, 50% aqueous sodium hydroxide solution was continuously added to ensure that the pH value of the reaction system was about 8.0. After that, the reaction system was cooled to 30°C and stirred for 48 hours, then 50% aqueous sodium hydroxide solution was added to adjust the pH to 8.5, and then extracted twice with 150 ml TBME, the organic phases were combined, and the organic phase was washed with 5% aqueous NaHCO ₃ solution Rinse (50 mL×3) and then with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was removed under reduced pressure to obtain yellow solid compound 1-5 (5.01 g, yield: 47%).

MS (ESI, pos.ion) m/z: 256.1 [M+H] ⁺ .

Step 4: Synthesis of Compounds 1-6

Compound 1-5 (14.57 g, 57 mmol) was dissolved in a mixed solvent of 100 mL of THF and 50 mL of methanol, cooled to 0° C., and then an aqueous solution (25 mL) of lithium hydroxide (4.79 g, 114 mmol) was added. , the reaction mixture was warmed to 30 °C and stirred overnight. The organic solvent was removed under reduced pressure to obtain a solid crude product, which was dissolved by adding 50 mL of ethyl acetate and 50 mL of water. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 12 g of crude product 1-6, which was directly carried out to the next reaction without further purification.

MS (ESI, pos.ion) m/z: 228.1 [M+H] ⁺ .

Step 5: Synthesis of Compounds 1-8

Compound 1-6 (1.00 g, 4.4 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and CDI (0.93 g, 5.7 mmol) was added thereto. The reaction mixture was heated to reflux and stirred for two hours. After the reaction was completed, it was cooled to room temperature, and compound 1-7 (0.80 g, 6.6 mmol) and DBU (1 mL, 6.6 mmol) were added, followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate, washed with 1N aqueous hydrochloric acid, and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 1-8 (0.94 g, yield: 65%).

MS (ESI, pos.ion) m/z: 331.1 [M+H] ⁺ .

Step 6: Synthesis of Compounds 1-9

Compound 1-8 (2.10 g, 6.3 mmol) was dissolved in 40 mL of isopropanol, p-toluenesulfonic acid (1.8 g, 9.4 mmol) was added thereto, the temperature was raised to 65° C., stirred for 4 hours, and cooled to room temperature, The organic solvent was removed under reduced pressure to obtain a white solid, which was rinsed with ethyl acetate and filtered to obtain compound 1-9 (1.49 g, yield: 80%)

¹ H NMR (400 MHz, CD ₃ OD): δ 7.73 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 5.81-5.65 (m, 1H), 5.44 (d, J=17.0Hz, 1H), 5.36 (d, J=10.3Hz, 1H), 3.13–2.96 (m, 1H), 2.47–2.32 (m, 4H), 2.20 (t, J=7.9Hz, 1H), 1.72 (t, J=9.0 Hz, 1H), 1.39-1.20 (m, 2H), 1.20-1.02 (m, 2H) ppm.

Example 2

synthetic route:

Step 1: Synthesis of Compound 2-1

Compound 2-0 (10.0 g, 72.4 mmol) was dissolved in 100 mL of methanol, and concentrated sulfuric acid (7 mL) was added thereto, then the temperature was raised to reflux, the reaction was performed for 18 hours, cooled to room temperature, and then concentrated under reduced pressure. The compound was dissolved in 100 mL of dichloromethane, then washed with 1N aqueous NaHCO ₃ solution (100 mL×2), the separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain compound 2- 1 (9.8 g, yield: 89%).

Step 2: Synthesis of Compounds 2-3

Compound 2-1 (3 g, 19.7 mmol) and compound 2-2 (2.63 g, 17.9 mmol) were dissolved in 50 mL of DMF, and K ₂ CO ₃ (2.96 g, 21.5 mmol) was added thereto. After the addition, the reaction The mixture was warmed to reflux and reacted overnight. After the reaction, the reaction system was cooled to room temperature, and then diluted with 100 mL of EtOAc. The resulting mixture was washed with H ₂ O (100 mL×2), and then washed with 50 mL of saturated brine once. The organic phase was dried with anhydrous Na ₂ SO ₄ . Filter and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain yellow solid compound 2-3 (4 g, yield: 78%).

MS(ESI, pos.ion) m/z: 274.1 [M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ8.05-7.99 (m, 1H), 7.99-7.93 (m, 1H), 7.61-7.53 (m, 1H), 7.50-7.42 (m, 1H), 7.33 ( q, J=7.2Hz, 1H), 7.16 (dt, J=11.8, 6.0Hz, 1H), 7.13 (d, J=8.2Hz, 1H), 6.84–6.76 (m, 1H), 3.76 (s, 3H) )ppm.

Step 3: Synthesis of Compounds 2-4

Compound 2-3 (4.10 g, 15 mmol) was dissolved in 100 mL of glacial acetic acid, then reduced iron powder (3.36 g, 60 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100 ml of 1N HCl solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 2-4 (2.8 g , Yield: 88%), directly proceed to the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.15 (s, 1H), 7.97 (dd, J=8.2, 1.7 Hz, 1H), 7.55 (td, J=8.1, 1.7 Hz, 1H), 7.34-7.21 (m, 2H), 7.21–7.10 (m, 2H), 7.06 (dt, J=4.0, 3.1 Hz, 1H).

Step 4: Synthesis of Compounds 2-6

Compound 2-4 (2.71 g, 12.8 mmol) was added to 50 mL of toluene, phosphorus oxychloride (1.3 mL, 14.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.65 mL, 14.0 mmol) was added slowly. 5.1 mmol). The temperature of the reaction mixture was raised to 110°C, and the reaction was carried out for 6 hours. After the reaction was completed, it was cooled to 0 °C, 5 mL of water was added to quench the reaction, then washed with 20 mL of water (20 mL×2), the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and reduced Concentrated under pressure to obtain crude product 2-6, which was directly carried out to the next step without purification.

Step 5: Synthesis of Compounds 2-8

Sodium hydride (0.37 g, 9.2 mmol) was added to 20 mL of anhydrous tetrahydrofuran, cooled to 0°C under nitrogen protection, and then an anhydrous tetrahydrofuran solution (5 mL) containing compound 2-7 (2.12 g, 9.2 mmol) was added Then, the temperature was raised to 30°C, and the mixture was stirred for two hours.

An anhydrous tetrahydrofuran solution (5 mL) containing compound 2-6 (1.07 g, 4.6 mmol) was added to the above reaction solution, followed by reaction overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 20 mL of water, washed once with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and then extracted with 20 mL of ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V) =1:1) purification to obtain white solid compound 2-8 (1.27 g, yield: 65%).

MS (ESI, pos.ion) m/z: 425.2 [M+H] ⁺ .

Step 6: Synthesis of Compounds 2-9

Compound 2-8 (0.85 g, 2.0 mmol), compound 1-9 (0.74 g, 1.8 mmol), EDCI (0.37 g, 1.9 mmol) and HOAT (0.27 g, 2.0 mmol) were added to a round-bottomed flask under nitrogen 15 mL of dichloromethane was added under protection, then cooled to 0 °C, DIPEA (0.8 mL, 4.6 mmol) was added, the temperature was raised to 30 °C, and stirred for 6 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, the resulting mixture was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and reduced in pressure After concentration, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 2-9 as a white solid (0.89 g, yield 70%).

MS(ESI, pos.ion) m/z: 637.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.13 (s, 1H), 7.49 (dd, J=22.8, 15.4 Hz, 2H), 7.35 (s, 1H), 7.21 (t, J=6.9 Hz, 3H) ), 7.18–7.09 (m, 3H), 5.89–5.75 (m, 2H), 5.29 (t, J=17.8Hz, 1H), 5.16 (d, J=10.4Hz, 1H), 3.74–3.48 (m, 2H), 2.96–2.81 (m, 1H), 2.54–2.50 (m, 2H), 2.42–2.25 (m, 1H), 2.14–2.10 (m, 2H), 2.03–1.95 (m, 1H), 1.46 ( s, 9H), 1.45–1.36 (m, 2H), 1.08 (dd, J=18.4, 7.5 Hz, 2H) ppm.

Step 7: Synthesis of Compounds 2-10

Compound 2-9 (0.75 g, 1.1 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then a 30% concentration of hydrochloric acid in ethyl acetate (10 mL) was added, and the reaction was stirred at room temperature for 2 hours . After completion of the reaction, filter, and rinse the filter cake with 20 ml of ethyl acetate to obtain compound 2-10 as a white solid, which is directly subjected to the next reaction without further purification.

MS(ESI, pos.ion) m/z: 537.2[M+H] ⁺ ;

¹ H NMR (600MHz, CD ₃ OD): δ 7.84-7.74 (m, 1H), 7.59 (t, J=7.4Hz, 1H), 7.32-7.12 (m, 6H), 5.92 (s, 1H), 5.73–5.56 (m, 1H), 5.37 (d, J=17.1Hz, 1H), 5.17 (d, J=10.3Hz, 1H), 4.73 (dd, J=23.9, 14.3Hz, 1H), 3.93–3.81 (m, 2H), 2.99–2.96 (m, 2H), 2.50–2.36 (m, 2H), 1.98–1.95 (m, 2H), 1.45–1.38 (m, 1H), 1.33–1.24 (m, 3H) , 1.24–1.16 (m, 1H), 1.16–1.03 (m, 2H) ppm.

Step 8: Synthesis of Compounds 2-12

Compound 2-10 (0.57 g, 0.99 mmol), compound 2-11 (0.54 g, 1.2 mmol), EDCI (0.23 g, 1.2 mmol) and HOAT (0.16 g, 1.2 mmol) were added to a round bottom flask under nitrogen Under protection, 8 mL of dichloromethane was added, then cooled to 0°C and DIPEA (0.52 mL, 3.0 mmol) was added. The temperature was raised to 30°C and stirred for 6 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with 10 mL of ethyl acetate (10 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and reduced in pressure The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 2-12 (0.47 g, yield 60%).

MS(ESI, pos.ion) m/z: 790.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.40-10.15 (m, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.22-7.08 (m ,6H),5.88(s,1H),5.77(ddt,J＝13.4,10.1,8.1Hz,2H),5.27(d,J＝17.2Hz,1H),5.12(d,J＝10.6Hz,1H) ,4.96(t,J＝14.9Hz,1H),4.91(d,J＝10.0Hz,1H),4.54-4.46(m,1H),4.46-4.37(m,1H),4.24(d,J＝11.7 Hz, 1H), 4.02 (dd, J=11.5, 3.5Hz, 1H), 2.98–2.87 (m, 1H), 2.57 (dt, J=24.3, 12.3Hz, 1H), 2.47–2.37 (m, 1H) , 2.23–2.12 (m, 1H), 2.03–1.90 (m, 4H), 1.77–1.66 (m, 1H), 1.57 (dt, J=25.4, 12.5Hz, 1H), 1.45–1.40 (m, 2H) , 1.40–1.27 (m, 15H), 1.22–1.08 (m, 2H), 1.08–0.93 (m, 2H) ppm.

Step 10: Synthesis of Compounds 2-13

Compound 2-12 (0.16 g, 0.21 mmol) was dissolved in 150 ml of 1,2-dichloroethane, 0.01 g of Grubbs second-generation catalyst was added under nitrogen protection, then the temperature was raised to 65 °C, and stirred at this temperature for 48 Hour. After the reaction was completed, the reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a white solid compound 2-13 (0.08 g, yield: 50%).

MS(ESI, pos.ion) m/z: 762.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.51 (d, J=56.6 Hz, 1H), 7.52-7.50 (m, 1H), 7.48-7.36 (m, 1H), 7.25 (d, J=6.5 Hz) ,1H),7.20–6.95(m,5H),6.00–5.85(m,1H),5.81–5.61(m,1H),5.05–4.94(m,1H),4.65(d,J=7.4Hz,1H ), 4.38(d, J=7.8Hz, 1H), 4.11-3.94(m, 1H), 2.90(s, 1H), 2.61-2.60(m, 3H), 2.35(q, J=8.5Hz, 1H) ,1.99–1.73(m,3H),1.54(dd,J=12.3,8.9Hz,1H),1.51–1.38(m,6H),1.37(s,9H),1.17–1.00(m,2H),0.99 –0.80(m,2H)ppm;

HPLC: 95.25%.

Example 3

synthetic route

Step 1: Synthesis of Compounds 3-3

Compound 3-1 (4 g, 21.9 mmol) and compound 2-2 (3.38 g, 24.0 mmol) were dissolved in 100 mL of DMF, and K ₂ CO ₃ (3.31 g, 24.0 mmol) was added, then the temperature was raised to reflux, and the reaction was performed overnight . After the reaction was completed, the reaction solution was cooled to room temperature, 200 mL of ethyl acetate was added, washed with H ₂ O (100 mL×2), and washed once with 50 mL of saturated brine. The organic phase was dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain 3-3 as a yellow solid (6.0 g, yield 90%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.98 (dd, J=8.2, 1.5 Hz, 1H), 7.56 (dd, J=7.9, 1.4 Hz, 1H), 7.43-7.36 (m, 1H), 7.33 (t, J=8.1Hz, 1H), 7.21 (dd, J=8.2, 1.2Hz, 1H), 7.14–7.03 (m, 1H), 6.67 (dd, J=8.4, 0.8Hz, 1H), 3.80 ( s, 3H), 3.76 (s, 3H) ppm.

Step 2: Synthesis of Compounds 3-4

Compound 3-3 (3.0 g, 9.9 mmol) was dissolved in 80 mL of glacial acetic acid, then iron powder (2.2 g, 39 mmol) was added, the temperature was raised to 115° C., and the mixture was stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100 ml of 1N HCl solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 3-4 (2.1 g, yield 88%), and proceeded to the next step without purification.

MS(ESI, pos.ion) m/z: 242.1[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.96 (s, 1H), 7.48 (d, J=7.1 Hz, 1H), 7.39 (dd, J=5.9, 3.2 Hz, 1H), 7.28 (s, 1H) ), 7.22–7.17 (m, 1H), 7.15 (dd, J=8.7, 5.8 Hz, 2H), 7.11–7.07 (m, 1H), 3.97 (s, 3H) ppm.

Step 3: Synthesis of Compounds 3-5

Compound 3-4 (0.5 g, 2.1 mmol) was added to 10 mL of toluene, phosphorus oxychloride (0.38 mL, 4.2 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.1 mL, 0.83 mmol) was added slowly mmol), the temperature was raised to 110 °C, and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, 2 mL of water was added to quench the reaction, and then washed with water (10 mL × 2). The organic phase was washed once with 10 mL of saturated brine, then dried over anhydrous sodium sulfate, filtered, and reduced The organic solvent was removed under reduced pressure to give crude product 3-5, which was carried on to the next step without further purification.

Step 4: Synthesis of Compounds 3-7

Sodium hydride (0.08 g, 2.1 mmol) was added to 10 mL of anhydrous tetrahydrofuran, cooled to 0°C under nitrogen protection, and then an anhydrous tetrahydrofuran solution (2 mL) containing compound 2-7 (0.24 g, 1.0 mmol) was added , then the temperature was raised to 30°C and stirred for two hours. An anhydrous tetrahydrofuran solution (2 mL) containing compound 3-5 (0.27 g, 1.0 mmol) was added to the above reaction solution, followed by reaction overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 10 mL of water, washed once with 10 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (10 mL×3) , the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1 : 1) Purification to obtain white solid compound 3-7 (0.28 g, yield 60%).

MS(ESI,neg.ion)m/z:453.2[MH] ^- ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.29 (s, 1H), 7.26-7.22 (m, 1H), 7.19-7.12 (m, 3H), 7.09 (dd, J=18.8, 7.4 Hz, 2H) ,5.81(d,J=28.1Hz,1H),4.02-3.87(m,5H),3.83(dd,J=12.2,4.2Hz,1H),2.83-2.59(m,2H),1.49(d,J =12.9Hz, 9H)ppm.

Step 5: Synthesis of Compounds 3-9

Compound 3-7 (0.2 g, 0.44 mmol), compound 1-9 (0.19 g, 0.48 mmol), EDCI (0.09 g, 0.48 mmol) and HOAT (0.07 g, 0.53 mmol) were added to a round bottom flask under nitrogen For protection, 4 mL of dichloromethane was added, then cooled to 0 °C and DIPEA (0.23 mL, 1.3 mmol) was added. The reaction was warmed to 30°C and stirred for 6 hours. After the reaction was completed, 5 mL of water was added to quench the reaction, extracted with ethyl acetate (15 mL×3), the organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 3-9 (0.11 g, yield 38%).

MS(ESI, pos.ion) m/z: 667.2[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.13 (s, 1H), 7.33-7.19 (m, 2H), 7.12-7.05 (m, 5H), 5.82 (dd, J=18.2, 9.0 Hz, 2H) ,5.32(d,J＝17.1Hz,1H),5.19(t,J＝11.6Hz,1H),4.41–4.30(m,1H),3.95(s,3H),3.93–3.80(m,2H), 2.97(s,1H), 2.62–2.48(m,2H), 2.19–2.17(m,1H), 2.02–1.97(m,1H), 1.48(s,9H), 1.42–1.31(m,2H), 1.06 (d, J=7.4 Hz, 2H) ppm.

Step 6: Synthesis of Compounds 3-10

Compound 3-9 (1.06 g, 1.5 mmol) was dissolved in 5 mL of ethyl acetate, cooled to 0 °C, and then 30% hydrochloric acid in ethyl acetate (20 mL) was added, and the reaction was stirred at room temperature for 2 hours . After filtration, the filter cake was washed with 10 ml of ethyl acetate to obtain compound 3-10 as a white solid. The obtained solid was directly subjected to the next reaction without further purification.

MS (ESI, pos.ion) m/z: 567.2 [M+H] ⁺ .

Step 7: Synthesis of Compounds 3-12

Compound 3-10 (0.80 g, 1.32 mmol), compound 2-11 (0.77 g, 1.71 mmol), EDCI (0.33 g, 1.77 mmol) and HOAT (0.23 g, 1.71 mmol) were added to a round bottom flask under nitrogen To protect, add dichloromethane (13 mL), then cool to 0 °C and add DIPEA (0.22 mL, 1.28 mmol). The reaction was warmed to 30°C and stirred for 6 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 3-12 (0.50 g, yield 46%).

MS(ESI, pos.ion) m/z: 820.3[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ): δ9.74(s,1H), 7.65(s,1H), 7.33-7.26(m,1H), 7.21-7.04(m,5H), 5.84-5.76(m, 2H), 5.71–5.59 (m, 1H), 5.37 (d, J=4.7Hz, 1H), 5.07–4.82 (m, 5H), 4.65 (dd, J=9.1, 3.1Hz, 1H), 4.52 (d , J=11.7Hz, 1H), 4.19 (d, J=4.2Hz, 1H), 3.98–3.94 (m, 2H), 3.93 (s, 3H), 2.93–2.91 (m, 1H), 2.65–2.62 ( m, 1H), 2.16–1.92 (m, 3H), 1.83–1.81 (m, 1H), 1.77–1.58 (m, 2H), 1.42–1.30 (m, 7H), 1.35 (s, 9H), 1.31– 1.19 (m, 5H), 1.07–1.01 (m, 2H) ppm.

Step 8: Synthesis of Compounds 3-13

Compound 3-12 (0.50 g, 0.61 mmol) was dissolved in 120 ml of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the temperature was raised to 65 °C and stirred at this temperature 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a white solid compound 3-13 (0.2 g, yield: 41%).

MS(ESI, pos.ion) m/z: 792.3[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ): δ 10.31(s, 1H), 7.30-7.28(m, 2H), 7.18-7.08(m, 3H), 7.08-7.05(m, 3H), 5.98(s, 1H), 5.73(dd, J=18.0, 8.7Hz, 1H), 5.25(s, 1H), 5.08–4.96(m, 1H), 4.61(s, 1H), 4.54(d, J=11.2Hz, 1H) ), 4.38(s, 1H), 4.11–4.00(m, 1H), 3.93(s, 1H), 2.97–2.87(m, 1H), 2.64(d, J=11.0Hz, 2H), 2.59(s, 1H), 2.33(t, J=8.7Hz, 1H), 1.91(s, 6H), 1.62-1.60(m, 1H), 1.54-1.39(m, 6H), 1.33(s, 9H), 1.21-1.12 (m,3H),0.97–0.88(m,1H)ppm;

HPLC purity: 94.99%.

Example 4

synthetic route:

Step 1: Synthesis of Compound 4-2

The substrate 2-chloronicotinic acid (3.15 g, 21.1 mmol) was dissolved in 100 mL of dichloromethane, cooled to 0 °C, under nitrogen protection, thionyl chloride (7.5 g, 63.3 mmol) was added, and then 2 drops were added dropwise. DMF, stirred for a while, warmed to reflux, and reacted overnight. When the reaction is complete, the reaction solution is concentrated under reduced pressure to obtain the crude product 4-2, and the obtained product is directly subjected to the next step without purification.

Step 2: Synthesis of Compounds 4-4

2-Chloronicotinoyl chloride (3.1 g, 21.1 mmol) was dissolved in 10 mL of ethyl acetate, then this solution was added to o-aminophenol (2.5 g, 23.2 mmol) and DIPEA (6.3 mL, 35.8 mmol) under nitrogen protection ) in ethyl acetate solution (100 mL), and stirred at 0 °C for about 1 hour. After the reaction was completed, 2 mL of water was added to quench the reaction, the organic phase was washed with 10 mL of saturated brine, and the organic solvent was spin-dried under reduced pressure. The obtained residue was dissolved in a mixed solvent of tetrahydrofuran:ethanol=1:1 (10mL:10mL), 10mL of 15% aqueous sodium hydroxide solution was added, and the reaction mixture was heated at 50°C for 1 hour, cooled to room temperature, and rotated off. 2/3 of the solvent. The pH was adjusted to 2 with 3N aqueous HCl, filtered, and the filter cake was dried in vacuo to obtain compound 4-4 as a brown solid (4.4 g, yield: 81%).

MS(ESI, pos.ion) m/z: 249.0 [M+H] ⁺ ;

¹ H NMR (600 MHz, DMSO-d ₆ ): δ 9.92-9.82 (m, 1H), 9.79 (d, J=16.8 Hz, 1H), 8.54-8.45 (m, 1H), 8.04 (dd, J= 7.5, 1.8Hz, 1H), 7.85 (d, J=7.9Hz, 1H), 7.56–7.44 (m, 1H), 7.06–6.99 (m, 1H), 6.90 (t, J=11.7Hz, 1H), 6.88-6.78(m,1H)ppm.

Step 3: Synthesis of Compounds 4-5

Compound 4-4 (4.4 g, 17.9 mmol) was dissolved in 100 mL of DMF, sodium hydroxide (0.86 g, 21.5 mmol) was added, and the reaction was warmed to 130° C. and stirred overnight. After the reaction was completed, 200 mL of ice water was added to quench the reaction, and a large amount of white solid was precipitated. After filtration, the filter cake was washed with 100 mL of water and then with 100 mL of ethanol to obtain compound 4-5 as a white solid (2.3 g, yield: 61.8%).

MS(ESI, pos.ion) m/z: 213.1 [M+H] ⁺ .

Step 4: Synthesis of Compounds 4-6

Compound 4-5 (0.64 g, 3.0 mmol) was added to 15 mL of toluene, phosphorus oxychloride (0.55 mL, 6.0 mmol) was added under nitrogen protection, and N,N-dimethylaniline (0.15 mL, 1.2 mmol) was added slowly mmol), the reaction temperature was raised to 110 °C, and the reaction was carried out for 6 hours. After the reaction was complete, it was cooled to 0°C, quenched by the addition of 2 mL of water, and then washed twice with 20 mL of water. The separated organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain crude product 4-6, which was directly carried out to the next step without further purification.

Step 5: Synthesis of Compounds 4-8

Sodium hydride (0.24 g, 6.0 mmol) was added to 10 mL of anhydrous tetrahydrofuran, cooled to 0 °C under nitrogen protection, and then 2 mL of anhydrous tetrahydrofuran solution containing compound 2-7 (0.69 g, 3.0 mmol) was added, and then The temperature was raised to 30°C and stirred for two hours.

2 mL of anhydrous tetrahydrofuran solution containing compound 4-6 (0.69 g, 3.0 mmol) was added to the above reaction solution, and then reacted overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 10 mL of water, washed once with 10 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (10 mL×3), Combine the organic phases. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) Purification gave compound 4-8 as a white solid (0.74 g, 56% yield).

MS(ESI,neg,ion)m/z: 424.2[MH] ^- .

Step 6: Synthesis of Compounds 4-10

Compound 4-8 (0.71 g, 1.67 mmol), compound 1-9 (0.80 g, 2.0 mmol), EDCI (0.38 g, 2.0 mmol) and HOAT (0.27 g, 2.0 mmol) were added to a round bottom flask under nitrogen 10 mL of dichloromethane was added under protection, then cooled to 0°C and DIPEA (1.2 mL, 6.68 mmol) was added. The reaction was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 4-10 (0.76 g, yield 71%).

MS(ESI, pos.ion) m/z: 638.2 [M+H] ⁺ .

Step 7: Synthesis of Compounds 4-11

Compound 4-10 (0.75 g, 1.2 mmol) was dissolved in 5 mL of ethyl acetate, cooled to 0° C., then 15 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was filtered, and the filter cake was rinsed with 10 ml of ethyl acetate to obtain compound 4-11 as a white solid, which was directly subjected to the next reaction without further purification.

Step 8: Synthesis of Compounds 4-12

Compound 2-11 (0.53 g, 1.18 mmol), compound 4-11 (0.32 g, 1.18 mmol), EDCI (0.23 g, 1.18 mmol) and HOAT (0.16 g, 1.18 mmol) were added to a round-bottomed flask under nitrogen 10 mL of dichloromethane was added under protection, then cooled to 0°C, and DIPEA (0.83 mL, 4.72 mmol) was added. The reaction was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic phase was washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1 ) was purified to give compound 4-12 as a pale yellow solid (0.40 g, 43% yield).

MS(ESI, pos.ion) m/z: 791.3 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.54 (d, J=7.6 Hz, 1H), 8.46-8.35 (m, 1H), 7.84 (d, J=5.8 Hz, 1H), 7.67 (d, J =7.9Hz,1H),7.43(dd,J=14.5,7.2Hz,2H),7.19(dd,J=7.5,5.0Hz,1H),6.04(s,1H),5.83–5.79(m,2H) ,5.38(d,J＝8.9Hz,1H),5.29(d,J＝17.3Hz,1H),5.16(d,J＝10.4Hz,1H),5.03(d,J＝1.8Hz,1H),4.96 (dd,J＝15.0,6.0Hz,2H),4.78(s,1H),4.40(s,1H),4.19(d,J＝12.1Hz,1H),4.08–3.97(m,1H),2.96– 2.94(m, 1H), 2.76(s, 1H), 2.52(s, 1H), 2.31–2.15(m, 1H), 2.09–1.96(m, 2H), 1.72(s, 1H), 1.63–1.60( m, 1H), 1.52–1.43 (m, 2H), 1.43–1.34 (m, 6H), 1.29 (d, J=10.3 Hz, 12H), 1.07 (d, J=7.4 Hz, 2H) ppm.

Step 9: Synthesis of Compounds 4-13

Compound 4-12 (0.07 g, 0.088 mmol) was dissolved in 30 mL of 1,2-dichloroethane, 0.007 g of Grubbs second-generation catalyst was added under nitrogen protection, the reaction was heated to 75 ° C, and stirred at this temperature 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a white solid compound 4-13 ( 0.065 g, yield: 97%).

MS(ESI, pos.ion) m/z: 763.3181[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.46 (d, J=7.0 Hz, 1H), 8.28 (d, J=3.4 Hz, 1H), 7.76 (d, J=5.0 Hz, 1H), 7.63 ( dd, J=16.9, 7.6Hz, 1H), 7.41–7.30(m, 2H), 7.08(s, 1H), 5.88(s, 1H), 5.52(d, J=7.4Hz, 1H), 5.45(d , J=7.7Hz, 1H), 5.21(s, 1H), 4.96–4.81(m, 1H), 4.55(s, 1H), 4.29(d, J=6.4Hz, 1H), 4.16(d, J= 10.5Hz, 1H), 2.75 (d, J=4.8Hz, 2H), 2.55 (s, 1H), 2.24–2.06 (m, 3H), 1.90 (s, 1H), 1.77 (m, 2H), 1.31– 1.24 (m, 8H), 1.19 (s, 9H), 1.13–1.07 (m, 2H), 0.90–0.85 (m, 2H), 0.83–0.77 (m, 1H) ppm;

HPLC purity: 95.64%.

Example 5

synthetic route:

Step 1: Synthesis of Compound 5-2

Compound 5-1 (8 g, 52 mmol) and o-fluoronitrobenzene (14.5 g, 103 mmol) were dissolved in DMF (200 mL), and K ₂ CO ₃ (21 mg, 156 mmol) was added, and the reaction was warmed to 120° C. overnight. After the reaction, the reaction solution was quenched by adding water, extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain orange. Compound 5-2 as a yellow oily liquid was directly carried out to the next step without purification.

Step 2: Synthesis of Compounds 5-3

Compound 5-2 (100 mg, 0.36 mmol) was dissolved in DMF (20 mL) and NaH (60% dispersed in mineral oil, 72 mg, 1.8 mmol) was added under ice bath. The reaction mixture was stirred at room temperature for 1 hour, then iodomethane (514 mg, 3.6 mmol) was added and the temperature was raised to 80°C and stirring was continued for 1 hour. After the reaction, the reaction solution was poured into 50 mL of water, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain yellow solid compound 5-3 (80 mg, yield 73%).

MS (ESI, pos.ion) m/z: 305.1 [M+H] ⁺ .

Step 3: Synthesis of Compounds 5-4

Compound 5-3 (50 mg, 0.16 mmol) was dissolved in glacial acetic acid (20 mL), iron powder (46 mg, 0.82 mmol) was added thereto, and the reaction mixture was warmed to 110° C. to react for 3 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was poured into 1N hydrochloric acid (50 mL), a solid was precipitated, filtered, and the filter cake was washed with water, and then dried to obtain a yellow solid compound 5-4 (38 mg, produced rate 98%).

MS (ESI, pos.ion) m/z: 243.1 [M+H] ⁺ .

Step 4: Synthesis of Compounds 5-5

Compound 5-4 (50 mg, 0.21 mmol) was added to toluene (20 mL), POCl ₃ (100 mg, 0.63 mmol) and N,N-dimethylaniline (14 mg, 0.11 mmol) were slowly added under stirring, after the addition The temperature was raised and refluxed for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 5-5 as a pale yellow solid (40 mg, yield 73%).

MS(ESI, pos.ion) m/z: 261.1 [M+H] ⁺ .

Step 6: Synthesis of Compounds 5-6

Compound N-Boc-4-(R)-hydroxyproline (53 mg, 0.23 mmol) was dissolved in DMF (10 mL), NaH (60% dispersed in mineral oil, 23 mg, 0.6 mmol) was added under ice bath, After the addition was complete, the reaction was warmed to room temperature and stirred for 2 hours.

Compound 5-5 (50 mg, 0.19 mmol) was dissolved in a small amount of DMF, added to the above reaction, and stirring was continued for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, and the pH value was adjusted to 2-3 with 1N HCl solution, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution, Dry over anhydrous sodium sulfate, filter, spin dry the organic solvent under reduced pressure, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a pale yellow solid compound 5- 6 (45 mg, 43% yield).

MS (ESI, pos.ion) m/z: 456.3 [M+H] ⁺ .

Step 7: Synthesis of Compounds 5-7

Compound 5-6 (50 mg, 0.11 mmol), compound 1-9 (44 mg, 0.11 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to CH ₂ Cl ₂ (15 mL) over ice DIPEA (48 mg, 0.37 mmol) was added under the bath, and after the addition was complete, the reaction was warmed to room temperature and stirred for 4 hours. After the reaction, the pH value of the reaction solution was adjusted to 2 with 1N aqueous hydrochloric acid solution, then extracted with dichloromethane (10 mL×2), and the organic phases were combined. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) After purification, compound 5-7 (42 mg, yield 63%) was obtained as a pale yellow solid.

Step 8: Synthesis of Compounds 5-9

Compound 5-7 (100 mg, 0.15 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure to obtain compound 5-8. Then compound 5-8 was added to 50 mL of CH ₂ Cl ₂ , followed by compound 2-11 (72 mg, 0.16 mmol), EDCI (46 mg, 0.24 mmol) and HOAT (33 mg, 0.24 mmol), and finally DIPEA was added under ice bath (12 mg, 0.48 mmol) and the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 5-9 (95 mg, 2:1) as a pale yellow solid. step yield 77%).

Step 9: Synthesis of Compounds 5-10

Compound 5-9 (200 mg, 0.24 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the temperature was raised to 75° C. for 48 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC to obtain compound 5-10 as a white solid (150 mg, yield 78%).

MS(ESI, pos.ion) m/z: 793.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.30 (s, 1H), 7.39 (s, 1H), 7.16-7.05 (m, 3H), 6.96 (d, J=7.8 Hz, 1H), 6.68 (d , J＝10.0Hz, 2H), 5.89(d, J＝41.8Hz, 1H), 5.73(d, J＝8.3Hz, 1H), 5.36-5.19(m, 1H), 5.01(d, J＝9.4Hz) ,1H),4.63(d,J＝55.8Hz,2H),4.42-4.32(m,1H),4.10-4.03(m,1H),3.22(s,3H),2.91(d,J＝16.2Hz, 1H), 2.61(s, 3H), 2.35(s, 1H), 1.88(d, J=52.8Hz, 4H), 1.62(s, 1H), 1.36(m, 17H), 1.13(d, J=32.7 Hz,2H),0.94(s,2H)ppm;

HPLC: 96.72%.

Example 6

synthetic route:

Step 1: Synthesis of Compound 6-2

The compound 4-bromo-2-fluorobenzaldehyde (15.0 g, 74 mmol) was dissolved in acetonitrile (30 mL), and NaH ₂ PO ₄ solution (1.78 g, 15 mmol was dissolved in 10 mL of water), H ₂ O ₂ were slowly added successively under ice bath. (11.8 mL, 104 mmol) and NaClO2 (9.37 _g , 104 mol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction solution was poured into 500 mL of water, a large amount of solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a white solid compound 6-2 (15.2 g, yield 93%).

Step 2: Synthesis of Compound 6-3

Compound 6-2 (6.6 g, 30 mmol) was dissolved in thionyl chloride (15 mL), and the reaction solution was refluxed under nitrogen protection for 2 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure. The obtained residue was dissolved in 30 mL of toluene, and the toluene was removed under reduced pressure, which was repeated twice to obtain compound 6-3 as a yellow oily liquid, and the next reaction was carried out directly without purification.

Step 3: Synthesis of Compounds 6-5

2-Aminothiophenol (5.6 g, 45 mmol) was dissolved in 40 mL of THF, and triethylamine (6.0 g, 60 mmol) and a THF solution (20 mL) containing compound 6-3 (7.1 g, 30 mmol) were slowly added under ice bath. ), after the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After the completion of the reaction, the reaction solution was poured into 100 mL of water, and the pH value was adjusted to about 4-5 with 1N HCl, a yellow solid was precipitated, filtered, and the filter cake was washed with 1N HCl aqueous solution and water successively, and the obtained solid was dried in vacuum, A pale yellow solid compound 6-5 was obtained (7.3 g, the total yield of step 1 and step 2 was 75%).

Step 4: Synthesis of Compounds 6-6

Compound 6-5 (5.2 g, 16 mmol) was dissolved in DMF (200 mL), K ₂ CO ₃ (11 g, 80 mmol) was added thereto, and the reaction mixture was refluxed for 5 hours. After the reaction was completed, the reaction mixture was poured into 500 mL of water, a yellow solid was precipitated, filtered, and the filter cake was washed successively with 50 mL of 1N NaOH aqueous solution and 50 mL of water, and the obtained solid was dried under vacuum to obtain a pale yellow solid compound 6-6 (3.6 g, 74% yield).

MS (ESI, pos.ion) m/z: 305.9 [M+H] ⁺ .

Step 5: Synthesis of Compounds 6-7

Compound 6-6 (2.5 g, 8 mmol) was suspended in toluene (30 mL), and POCl (2.5 g, 16 mmol) and N,N-dimethylaniline (0.4 g, ₃ mmol) were slowly added under stirring. , the reaction mixture was heated to reflux for 3 hours. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether) to obtain compound 6-7 as a pale yellow solid (1.5 g, yield 57%).

MS (ESI, pos.ion) m/z: 325.9 [M+H] ⁺ .

Step 6: Synthesis of Compounds 6-8

The compound N-Boc-4-(R)-hydroxyproline methyl ester (1.3 g, 5.3 mmol) was dissolved in DMF (50 mL), and NaH (60% dispersed in mineral oil, 0.37 mL) was added in portions under ice bath g, 9.2 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes.

Compound 6-7 (1.56 g, 4.8 mmol) was dissolved in a small amount of DMF, and the resulting solution was added to the above solution, and the reaction mixture was stirred for a further 2 hours. After the reaction, the reaction solution was poured into 300 mL of water, and the pH value was adjusted to 2-3 with 1N HCl aqueous solution, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution, It was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 6-8 (1.0 g, 42% yield). MS (ESI, neg.ion) m/z: 516.9 [MH] ^- .

Step 7: Synthesis of Compounds 6-9

Compound 6-8 (1.0 g, 1.9 mmol), compound 1-9 (0.8 g, 1.9 mmol), EDCI (0.5 g, 2.5 mmol) and HOAT (0.3 g, 2.1 mmol) were added to CH ₂ Cl ₂ (30 mL) ), DIPEA (0.9 mL, 5.0 mmol) was added under an ice bath, and after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 6-9 as a pale yellow solid (1.1 g, yield 78%).

MS (ESI, pos.ion) m/z: 731.0 [M+H] ⁺ .

Step 8: Synthesis of Compounds 6-11

Compound 6-9 (850 mg, 1.16 mmol) was added to 5N HCl in EtOAc (30 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction, the solvent was evaporated under reduced pressure to obtain compound 6-10 as a white solid. Then compound 6-10 was added to 30 mL of CH ₂ Cl ₂ , followed by compound 2-11 (578 mg, 1.28 mmol), EDCI (290 mg, 1.51 mmol) and HOAT (170 mg, 1.28 mmol), under ice bath, and then added DIPEA (0.6 mL, 3.48 mmol), the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 6-11 as a pale yellow solid (220 mg, yield 22 %).

MS (ESI, neg.ion) m/z: 629.1 [MH] ^- .

Step 9: Synthesis of Compounds 6-12

Compound 6-11 (220 mg, 0.25 mmol) was dissolved in 1,2-dichloroethane (200 mL), Grubbs second-generation catalyst (20 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 6-12 (40 mg, yield: 19%) as a white solid.

MS(ESI, pos.ion) m/z: 856.8[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.31 (s, 1H), 7.65 (s, 1H), 7.48-7.36 (m, 3H), 7.31 (d, J=7.3 Hz, 1H), 7.21 (d , J=7.6Hz, 1H), 7.15–7.02 (m, 1H), 5.93 (s, 1H), 5.80–5.58 (m, 1H), 5.21 (d, J=7.0Hz, 1H), 5.00 (t, J=9.2Hz, 1H), 4.62(t, J=7.5Hz, 2H), 4.37(t, J=7.5Hz, 1H), 4.05(d, J=8.0Hz, 1H), 2.92(s, 1H) ,2.72–2.52(m,3H),2.35–2.28(m,1H),1.95–1.82(m,6H),1.65–1.22(m,15H),1.17–1.08(m,2H),0.97–0.85( m,2H)ppm.

Example 7

synthetic route

Step 1: Synthesis of Compounds 7-3

Compound 4-bromo-2-fluoronitrobenzene (3.30 g, 15 mmol), 4-methoxybenzeneboronic acid (2.74 g, 18 mmol), Pd(PPh ₃ ) ₄ (0.5 g, 0.45 mmol) and K ₂ CO ₃ (10.35 g, 75 mmol) was dissolved in a mixed solvent of THF (80 mL) and water (20 mL), and the reaction mixture was stirred overnight at room temperature under nitrogen protection. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a yellow solid compound 7-3 (3.2 g, yield 87%).

MS (ESI, pos.ion) m/z: 248.2 [M+H] ⁺ .

Step 2: Synthesis of Compounds 7-5

Compound 7-3 (2.8 g, 11.3 mmol) and compound 7-5 (1.9 g, 12.5 mmol) were dissolved in DMF (50 mL), then K ₂ CO ₃ (3.1 g, 22.6 mmol) was added, and the reaction mixture was warmed to 110 °C reaction overnight. After the reaction, 100 mL of water was added to quench the reaction, the pH value was adjusted to 2-3 with 1N HCl aqueous solution, and then extracted with ethyl acetate (50 mL×3), the combined organic phases were washed with saturated sodium chloride solution, and anhydrous Dry over sodium sulfate, filter, and evaporate the organic solvent under reduced pressure to obtain compound 7-5 as an orange-yellow oily liquid, which is directly subjected to the next reaction without further purification.

MS (ESI, pos.ion) m/z: 382.1 [M+H] ⁺ .

Step 3: Synthesis of Compounds 7-6

Compound 7-5 was dissolved in glacial acetic acid (300 mL), and iron powder (2.8 g, 56.5 mmol) was added thereto, and the reaction mixture was heated to 110° C. to react for 8 hours. After the reaction was completed, it was cooled to room temperature, then filtered, the filtrate was concentrated and poured into 300 mL of water, a solid was precipitated, filtered, and the filter cake was washed with water, and then dried to obtain a yellow solid compound 7-6 (3.6 g, two steps 2 and 3). step yield 95%).

MS (ESI, pos.ion) m/z: 334.1 [M+H] ⁺ .

Step 4: Synthesis of Compounds 7-7

Compound 7-6 ((3.5 g, 10.5 mmol) was dissolved in toluene (30 mL), POCl ₃ (3.2 g, 21 mmol) and N,N-dimethylaniline (0.51 g, 4.2 mmol) were slowly added with stirring, After the addition, the reaction solution was heated and refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain a pale yellow solid compound 7-7 (1.2 g, yield 33%). ).

Step 5: Synthesis of Compounds 7-8

Compound N-Boc-4-(R)-hydroxyproline (0.87 g, 3.75 mmol) was dissolved in DMF (20 mL), and NaH (60% dispersed in mineral oil, 0.30 g, 7.5 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. Compound 7-7 (1.2 g, 3.42 mmol) was dissolved in a small amount of DMF, and the resulting solution was added to the above reaction solution, and stirring was continued for 2 hours. After the reaction, pour the reaction solution into 300 mL of water, adjust the pH value to 2-3 with 1N HCl aqueous solution, then extract with ethyl acetate (50 mL×3), combine the organic phases,

The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1 ) was purified to obtain compound 7-8 as a pale yellow solid (1.7 g, yield 83%).

MS (ESI, neg.ion) m/z: 547.2 [M+H] ⁻ .

Step 6: Synthesis of Compounds 7-9

Compound 7-8 (1.2 g, 2.2 mmol), compound 1-9 (0.97 g, 2.4 mmol), EDCI (546 mg, 2.9 mmol) and HOAT (324 mg, 2.4 mmol) were suspended in CH ₂ Cl ₂ (30 mL) , DIPEA (1.0 mL, 5.7 mmol) was added under an ice bath. After the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, 5 mL of 1N aqueous hydrochloric acid was added to quench the reaction, then extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to reduced pressure. The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 7-9 as a pale yellow solid (1.2 g, yield 72%).

MS (ESI, pos.ion) m/z: 759.2 [M+H] ⁺ .

Step 7: Synthesis of Compounds 7-11

Compound 7-9 (600 mg, 0.8 mmol) was dissolved in 5N HCl in EtOAc (15 mL), and the reaction solution was stirred at room temperature for 3 hours.

After the reaction, the solvent was evaporated under reduced pressure to obtain compound 7-10 as a white solid.

Compound 7-10 was added to CH ₂ Cl ₂ (20 mL), followed by compound 2-11 (434 mg, 0.96 mmol), EDCI (200 mg, 1.04 mmol) and HOAT (120 mg, 0.88), followed by DIPEA under ice bath (0.22 mL, 1.28 mmol), the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 7-11 as a pale yellow solid (410 mg, yield 57 %).

MS(ESI, pos.ion) m/z: 912.2 [M+H] ⁺ .

Step 8: Synthesis of Compounds 7-12

Compound 7-11 (400 mg, 0.44 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 65° C. for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 7-12 (110 mg, yield 28%) as a white solid.

MS(ESI, pos.ion) m/z: 884.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.32 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.54-7.44 (m, 5H), 7.43-7.34 (m, J=10.7, 4.4Hz, 1H), 7.31–7.25(m, 2H), 6.97(d, J=8.8Hz, 2H), 5.98(s, 1H), 5.74(dd, J=18.0, 8.7Hz, 1H), 5.26( s, 1H), 5.01 (t, 1H), 4.82–4.52 (m, 2H), 4.41 (t, J=7.5Hz, 1H), 4.14–4.03 (m, 1H), 3.86 (s, 3H), 2.98 –2.88(m,1H),2.73–2.51(m,3H),2.42–2.26(m,1H),1.98–1.75(m,6H),1.61–1.31(m,15H),1.18–1.08(m, 2H), 1.00–0.85 (m, 2H) ppm.

Example 8

synthetic route:

Step 1: Synthesis of Compound 8-2

Compound 8-1 (2.3 g, 7.2 mmol) was added to 50 mL of toluene, phosphorus oxychloride (1.32 mL, 14.4 mmol) was added under nitrogen protection, and N,N-dimethylaniline (0.36 mL, 2.88 mmol) was added slowly mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0°C, and 10 mL of water was added to quench the reaction. The obtained mixture was washed with water (30 mL×2), the separated organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then reduced The organic solvent was removed under pressure to obtain compound 8-2, which was directly carried out to the next step without further purification.

Step 2: Synthesis of Compound 8-3

Sodium hydride (0.58 g, 14.4 mmol) was added to 40 mL of anhydrous tetrahydrofuran, cooled to 0°C under nitrogen protection, and then 10 mL of anhydrous tetrahydrofuran solution containing compound 2-7 (0.24 g, 1.0 mmol) was added. After completion, the reaction mixture was warmed to 30°C and stirred for two hours.

A solution of compound 8-2 (2.4 g, 7.2 mmol) in 10 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then reacted overnight. After the reaction was completed, the reaction was quenched with 30 mL of water at 0°C, and washed with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 8-4 (1.2 g, yield 31%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.57 (dd, J=16.5, 8.5 Hz, 3H), 7.47-37 (m, 2H), 7.26-7.05 (m, 4H), 6.95 (m, 2H) , 5.81 (s, 1H), 4.07–3.94 (m, 2H), 3.95 (s, 3H), 2.68–2.72 (m, 2H), 1.61–1.36 (m, 9H) ppm.

Step 3: Synthesis of Compounds 8-4

Compound 8-3 (0.94 g, 1.8 mmol), compound 1-9 (0.78 g, 1.95 mmol), EDCI (0.44 g, 2.3 mmol) and HOAT (0.26 g, 1.95 mmol) were added to a round-bottomed flask under nitrogen Under protection, 15 mL of dichloromethane was added, then cooled to 0°C, and then DIPEA (1.08 mL, 6.2 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, then extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain yellow solid compound 8-4 (0.85 g, yield 65%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.24-10.01 (m, 1H), 7.56 (d, J=8.5 Hz, 3H), 7.50-7.34 (m, 2H), 7.30-7.12 (m, 4H) ,7.01(d,J＝8.6Hz,2H),5.96-5.75(m,2H),5.35(t,J＝19.5Hz,1H),5.26-5.04(m,1H),4.37(s,1H), 3.98–3.81 (m, 4H), 2.98 (s, 1H), 2.57 (d, J=17.4Hz, 2H), 2.28–2.13 (m, 1H), 1.99 (d, J=37.9Hz, 1H), 1.47 (d, J=29.9 Hz, 9H), 1.42-1.31 (m, 2H), 1.12-0.96 (m, 2H) ppm.

Step 4: Synthesis of Compounds 8-5

Compound 8-4 (1.06 g, 1.5 mmol) was dissolved in 5 mL of ethyl acetate, cooled to 0°C, then 30% hydrochloric acid in ethyl acetate solution (20 mL) was added, and stirred at room temperature until no gas The reaction was terminated when released. The reaction mixture was filtered, and the filter cake was rinsed with 10 mL of ethyl acetate to obtain compound 8-5 as a white solid, which was directly subjected to the next reaction without further purification.

MS(ESI, pos.ion) m/z: 643.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CD ₃ OD): δ 7.75 (dd, J=8.0, 5.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.58–7.47 (m, 2H), 7.30– 7.15(m, 4H), 7.05(d, J=8.8Hz, 2H), 5.94(s, 1H), 5.77–5.63(m, 1H), 5.36(d, J=17.0Hz, 1H), 5.19(d , J=10.4Hz, 1H), 4.66 (d, J=7.5Hz, 1H), 3.87 (s, 4H), 3.05–2.92 (m, 2H), 2.48–2.28 (m, 2H), 2.06–1.95 ( m, 2H), 1.42 (dd, J=9.6, 5.6 Hz, 1H), 1.35–1.26 (m, 2H), 1.26–1.03 (m, 3H) ppm.

Step 5: Synthesis of Compounds 8-6

Compound 8-5 (0.48 g, 0.72 mmol), compound 2-11 (0.42 g, 0.93 mmol), EDCI (0.18 g, 0.93 mmol) and HOAT (0.13 g, 0.93 mmol) were added to a round bottom flask under nitrogen 10 mL of dichloromethane was added under protection, then cooled to 0°C and DIPEA (0.5 mL, 2.86 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure , the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 8-6 (0.35 g, yield 54%).

Step 6: Synthesis of Compounds 8-7

Compound 8-6 (0.31 g, 0.35 mmol) was dissolved in 100 mL of 1,2-dichloroethane, 0.03 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the temperature was raised to 65 °C, and stirred at this temperature for 48 Hour. Cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 8-7 (0.1 g, yield rate: 33%).

MS(ESI, pos.ion) m/z: 868.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.33 (s, 1H), 7.55-7.48 (m, 3H), 7.39-7.28 (m, 3H), 7.23-7.06 (m, 3H), 7.00 (d, J=8.2Hz, 2H), 5.99(s, 1H), 5.73(dd, J=18.1, 8.7Hz, 1H), 5.24(d, J=7.2Hz, 1H), 5.05–4.96(m, 1H), 4.61–4.562 (m, 2H), 4.38–4.10 (t, J=7.7Hz, 1H), 4.10 (dd, J=20.4, 8.5Hz, 1H), 3.86 (d, J=11.2Hz, 3H), 3.00 –2.86(m,1H),2.66(s,2H),2.57(s,1H),2.34(m,2H),2.04–1.84(m,6H),1.74-1.51(m,1H),1.41–1.28 (m, 12H), 1.20-1.04 (m, 3H), 0.94 (pd, J=13.6, 8.4 Hz, 2H) ppm.

Example 9

synthetic route:

Step 1: Synthesis of Compounds 9-3

Compound 9-1 (50 mg, 0.29 mmol) and compound 2-2 (50 mg, 0.35 mmol) were dissolved in DMF (20 mL), and K ₂ CO ₃ (60 mg, 0.44 mmol) was added thereto, and the reaction mixture was warmed to 110° C. React overnight. After the reaction was completed, 20 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound 9-3 as an orange oily liquid, which was directly subjected to the next reaction without purification.

MS (ESI, pos.ion) m/z: 292.1 [M+H] ⁺ .

Step 2: Synthesis of Compounds 9-4

Compound 9-3 (1 g, 3.4 mmol) was dissolved in glacial acetic acid (50 mL), iron powder (0.96 g, 17.2 mmol) was added thereto, and the temperature was raised to 110° C. to react for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the obtained filtrate was poured into 100 mL of 1N aqueous hydrochloric acid solution, a solid was precipitated, filtered, and the filter cake was washed with water, and then dried to obtain a yellow solid compound 9-4 (0.6 g, 77% yield for both steps 1 and 2).

Step 3: Synthesis of Compounds 9-5

Compound 9-4 (50 mg, 0.22 mmol) was suspended in toluene (20 mL), and POCl ₃ (100 mg, 0.66 mmol) and N,N-dimethylaniline (13 mg, 0.11 mmol) were slowly added under stirring. , the reaction was heated and refluxed for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 9-5 (42 mg, yield 77%) as a pale yellow solid.

MS(ESI, pos.ion) m/z: 248.1 [M+H] ⁺ .

Step 4: Synthesis of Compounds 9-6

Compound N-Boc-4-(R)-hydroxyproline (60 mg, 0.24 mmol) was dissolved in DMF (10 mL), and NaH (60%, 25 mg, 0.6 mmol) was added under ice bath. Stir to room temperature for 2 hours. Compound 2-7 (60 mg, 0.24 mmol) was dissolved in a small amount of DMF, added to the above reaction solution, and stirring was continued for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, the pH value was adjusted to 2-3 with 1N HCl aqueous solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride solution , dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a pale yellow solid compound 9-6 (93 mg , the yield is 87%).

MS(ESI, pos.ion) m/z: 342.2[M-99] ⁺ .

Step 5: Synthesis of Compounds 9-7

Compound 9-6 (50 mg, 0.11 mmol), compound 1-9 (45 mg, 0.11 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were suspended in CH ₂ Cl ₂ (15 mL) over ice DIPEA (48 mg, 0.37 mmol) was added under the bath, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the pH value of the reaction mixture was adjusted to 2 with 1N aqueous hydrochloric acid, extracted with dichloromethane (10ml×3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 9-7 (588 mg, yield 82%) as a pale yellow solid.

MS (ESI, pos.ion) m/z: 655.2 [M+H] ⁺ .

Step 6: Synthesis of Compounds 9-9

Compound 9-7 (1.15 g, 1.8 mmol) was dissolved in 5N HCl in EtOAc (30 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue was diluted with CH ₂ Cl ₂ (50 mL), then compound 2-11 (814 mg, 1.8 mmol), EDCI (546 mg, 2.85 mmol) and HOAT (388 mg, 2.85 mmol) were added, and DIPEA (924 mg) was added under ice bath. , 7.15 mmol), then the reaction was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 9-9 (726 mg, step 5 and 2:1) as a pale yellow solid. Step 6, two-step yield 50%).

MS (ESI, pos.ion) m/z: 808.3 [M+H] ⁺ .

Step 7: Synthesis of Compounds 9-10

Compound 9-9 (230 mg, 0.28 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 75° C. for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain a white solid compound 9-10 (160 mg, yield 73%).

MS(ESI, pos.ion) m/z: 780.3079[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.36 (s, 1H), 7.56 (d, J=6.6 Hz, 1H), 7.26-7.10 (m, 4H), 6.88 (dd, J=33.8, 7.3 Hz ,2H),5.92(s,1H),5.72(dd,J=17.5,8.6Hz,1H),5.32–5.24(m,1H),5.00(t,J=9.3Hz,1H),4.77–4.46( m, 2H), 4.35(t, J=7.7Hz, 1H), 4.07(dd, J=48.2, 10.0Hz, 1H), 2.92(s, 1H), 2.73–2.49(m, 3H), 2.34(d , J=8.1Hz, 1H), 1.98–1.75 (m, 4H), 1.58 (s, 1H), 1.51–1.27 (m, 18H), 1.19–1.05 (m, 2H), 0.98–0.89 (m, 1H) )ppm;

HPLC: 97.52%.

Example 10

synthetic route:

Step 1: Synthesis of Compound 10-3

Combine penta-4-bromo-2-fluoronitrobenzene (1.10 g, 5 mmol), 4-fluorobenzeneboronic acid (0.84 g, 6 mmol), Pd(PPh ₃ ) ₄ (0.58 g, 0.5 mmol) and K ₂ CO ₃ (3.45 g, 25 mmol) was added to a mixed solvent of THF (30 mL) and water (5 mL), and the reaction mixture was refluxed overnight under nitrogen protection. After the reaction, saturated sodium chloride solution (100 mL) was added to quench the reaction, extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The organic solvent was removed to obtain yellow solid compound 10-3 (1.0 g, yield 85%).

Step 2: Synthesis of Compound 10-5

Compounds 10-3 (1.0 g, 4.3 mmol) and 10-4 (0.65 g, 4.3 mmol) were dissolved in DMF (20 mL), and K ₂ CO ₃ (1.19 g, 8.6 mmol) was added thereto, and the reaction mixture was warmed to The reaction was carried out at 110°C overnight. After the reaction, 20 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The compound 10-5 was obtained as an orange oily liquid, and the next reaction was carried out directly without further purification.

MS (ESI, pos.ion) m/z: 368.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 10-6

Compound 10-5 was dissolved in glacial acetic acid (50 mL), iron powder (1.12 g, 20 mmol) was added, and the temperature was raised to 110° C. to react for 8 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was poured into water (150 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a yellow solid compound 10-6 (1.1 g, collected in two steps from step 2 and step 3). rate 84%).

MS (ESI, pos.ion) m/z: 306.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 10-7

Compound 10-6 (1.0 g, 3.3 mmol) was dissolved in toluene (20 mL), POCl ₃ (1.0 g, 6.6 mmol) and N,N-dimethylaniline (0.16 g, 1.3 mmol) were slowly added with stirring, After the addition, the reaction mixture was heated and refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 10-7 as a pale yellow solid (0.68 g, yield 64%).

MS(ESI, pos.ion) m/z: 324.1 [M+H] ⁺ .

Step 5: Synthesis of Compound 10-8

The compound N-Boc-4-(R)-hydroxyproline (0.58 g, 2.5 mmol) was dissolved in DMF (15 mL), and NaH (60% dispersed in mineral oil, 0.25 mL) was added in portions under ice bath. g, 6.3 mmol), after the addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. Compound 10-7 (0.68 g, 2.1 mmol) was dissolved in a small amount of DMF and added to the above reaction solution, and the reaction was continued to stir for 12 hours. After the reaction, the reaction solution was poured into 100 mL of water, and the pH value was adjusted to 2-3 with 1N HCl aqueous solution, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution, Dry over anhydrous sodium sulfate, filter, spin dry the organic solvent under reduced pressure, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 10-8 as a pale yellow solid (0.90 g, 83% yield).

MS (ESI, pos.ion) m/z: 519.1 [M+H] ⁺ .

Step 6: Synthesis of Compound 10-9

Compound 10-8 (900 mg, 1.74 mmol, compound 1-9 (768 mg, 1.91 mmol), EDCI (432 mg, 2.26 mmol) and HOAT (258 mg, 1.91 mmol) were added to CH ₂ Cl ₂ (20 mL), ice bath DIPEA (0.8 mL, 4.52 mmol) was added down, and after the addition, the reaction mixture was raised to room temperature and stirred for 4 hours. After the reaction was completed, the organic solvent was spin-dried under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate) The ester (V:V)=2:1) was purified to obtain compound 10-9 as a pale yellow solid (1.0 g, yield 79%).

MS(ESI, pos.ion) m/z: 731.2 [M+H] ⁺ .

Step 7: Synthesis of Compounds 10-11

Compound 10-9 (1.0 g, 1.37 mmol) was dissolved in 5N HCl in ethyl acetate (20 mL), and the reaction solution was stirred at room temperature for 3 hours. After the reaction, the solvent was evaporated under reduced pressure to obtain compound 10-10 as a white solid. The obtained solid compound 10-10 was diluted with CH ₂ Cl ₂ (20 mL), then compound 2-11 (610 mg, 1.35 mmol), EDCI (278 mg, 1.46 mmol) and HOAT (182 mg, 1.35) were added, and DIPEA was added under ice bath. (0.6 mL, 3.36 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 10-11 as a pale yellow solid (660 mg, yield 54%).

Step 8: Synthesis of Compounds 10-12

Compound 10-11 (600 mg, 0.68 mmol) was dissolved in 1,2-dichloroethane (500 mL), Grubbs second-generation catalyst (80 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and the crude product was purified by preparative HPLC to obtain compound 10-12 (400 mg, yield 68%) as a white solid.

HRMS (ESI, pos.ion) m/z: 856.3 [M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.36(s,1H), 7.66-7.40(m,4H), 7.39-7.26(m,3H), 7.24-7.18(m,1H), 7.14(d, J=9.0Hz, 3H), 5.95(s, 1H), 5.73(d, J=8.4Hz, 1H), 5.30(d, J=6.3Hz, 1H), 5.01(t, J=9.1Hz, 1H) ,4.78–4.47(m,2H),4.38(s,1H),4.13–3.98(m,1H),2.93(s,1H),2.77–2.49(m,3H),2.42–2.29(m,1H) , 2.04–1.75 (m, 4H), 1.60 (s, 1H), 1.51–1.26 (m, 16H), 1.22–1.06 (m, 2H), 1.06–0.72 (m, 2H) ppm.

Example 11

synthetic route:

Step 1: Synthesis of Compound 11-3

Compound 4-bromo-2-fluoronitrobenzene (3.30 g, 15 mmol), 4-methoxybenzeneboronic acid (2.74 g, 18 mmol), Pd(PPh ₃ ) ₄ (0.5 g, 0.45 mmol) and K ₂ CO ₃ (10.35 g, 75 mmol) was dissolved in a mixed solvent of THF (80 mL) and water (20 mL), and the reaction mixture was stirred at room temperature under nitrogen protection overnight. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), the organic phases were combined, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. , the solvent was evaporated under reduced pressure to obtain yellow solid compound 11-3 (3.2 g, yield 87%).

MS (ESI, pos.ion) m/z: 248.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 11-5

Compound 11-3 (1.83 g, 7.4 mmol) and compound 11-4 (1.13 g, 7.4 mmol) were dissolved in DMF (20 mL), and K ₂ CO ₃ (1.12 g, 8.1 mmol) was added thereto, and the reaction mixture was warmed up The reaction was carried out at 110°C overnight. After the reaction was completed, 20 mL of water was added to quench the reaction, the pH was adjusted to 2-3 with 1N HCl aqueous solution, and then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride solution Washed, dried over anhydrous sodium sulfate, filtered, and the organic solvent was evaporated under reduced pressure to obtain compound 11-5 as an orange oily liquid, which was directly carried out to the next step without purification.

MS (ESI, pos.ion) m/z: 380.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 11-6:

The crude product of compound 11-5 was dissolved in glacial acetic acid (100 mL), then iron powder (2.1 g, 37 mmol) was added, and the reaction temperature was raised to 110° C. for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was poured into water (200 mL), a solid was precipitated, filtered, and the filter cake was washed with water, and then dried to obtain a yellow solid compound 11-6 (1.57 g, step 2 and Step 3 yield 67%)

MS (ESI, pos.ion) m/z: 318.1 [M+H] ⁺ .

Step 4: Synthesis of Compounds 11-7

Compound 11-6 (1.4 g, 4.4 mmol) was suspended in toluene (20 mL), POCl ₃ (1.3 g, 8.8 mmol) and N,N-dimethylaniline (0.21 g, 1.8 mmol) were slowly added with stirring, After the addition, the reaction mixture was heated and refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 11-7 (1.04 g, yield 66%) as a pale yellow solid.

MS (ESI, pos.ion) m/z: 336.0 [M+H] ⁺ .

Step 5: Synthesis of Compounds 11-8

Compound N-Boc-4-(R)-hydroxyproline (0.76 g, 3.29 mmol) was dissolved in DMF (20 mL), and NaH (60% dispersed in mineral oil, 0.35 g, 8.94 mL) was added in portions under ice bath mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. Compound 11-7 (1.0 g, 2.98 mmol) was dissolved in a small amount of DMF, added to the above reaction, and stirring was continued for 2 hours. After the reaction, the reaction solution was poured into 30 mL of water, the pH value was adjusted to 2-3 with 1N HCl aqueous solution, extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride solution , dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 11-8 ( 1.5g, yield 95%).

MS (ESI, pos.ion) m/z: 531.1 [M+H] ⁺ .

Step 6: Synthesis of Compounds 11-9

Compound 11-8 (530 mg, 1.0 mmol), compound 1-9 (442 mg, 1.1 mmol), EDCI (248 mg, 1.3 mmol) and HOAT (150 mg, 1.1 mmol) were suspended in CH ₂ Cl ₂ (15 mL) over ice DIPEA (0.6 mL, 2.6 mmol) was added under the bath, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 11-9 (670 mg, yield) as a pale yellow solid. rate 90%).

MS (ESI, pos.ion) m/z: 743.2 [M+H] ⁺ .

Step 7: Synthesis of Compounds 11-11

Compound 11-9 (670 mg, 0.90 mmol) was dissolved in 5N HCl in ethyl acetate (15 mL), and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was diluted with that _CH2Cl2 (15 mL), then compound _2-11 (488 mg, 1.08 mmol), EDCI (223 mg, 1.17 mmol) and HOAT (146 mg, 1.08) were added, DIPEA (0.47 mL) was added under ice bath , 2.70 mmol), then the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 11-11 (320 mg, yield) as a pale yellow solid 40%).

MS (ESI, pos.ion) m/z: 896.3 [M+H] ⁺ .

Step 8: Synthesis of Compounds 11-12

Compound 11-11 (300 mg, 0.34 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 65° C. for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 11-12 (100 mg, yield 34%) as a white solid.

MS(ESI, pos.ion) m/z: 868.4[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.34 (s, 1H), 7.61-7.53 (m, 2H), 7.51-7.41 (m, 1H), 7.40-7.32 (m, 2H), 7.30-7.28 ( m, 1H), 7.21 (d, J=7.9Hz, 1H), 7.19–7.06 (m, 2H), 6.98 (d, J=8.7Hz, 2H), 5.97 (s, 1H), 5.74 (dd, J =18.1,8.7Hz,1H),5.35-5.14(m,1H),5.10-4.95(m,1H),4.87-4.45(m,2H),4.38(t,J=7.7Hz,1H),4.06( d, J=11.6Hz, 1H), 3.87 (s, 3H), 3.01–2.80 (m, 1H), 2.76–2.45 (m, 3H), 2.35 (q, J=8.6Hz, 1H), 2.02–1.76 (m, 6H), 1.72–1.23 (m, 15H), 1.18–1.06 (m, 2H), 0.98–0.86 (m, 2H) ppm;

HPLC purity: 95.35%.

Example 12

synthetic route:

Step 1: Synthesis of Compound 12-3

Compound 5-bromo-2-fluoronitrobenzene (1.0 g, 4.5 mmol), 4-methoxybenzeneboronic acid (0.75 g, 5.4 mmol), Pd(PPh ₃ ) ₄ (0.52 g, 0.45 mmol) and K ₂ CO ₃ (1.24 g, 9 mmol) was dissolved in a mixed solvent of THF (24 mL) and water (6 mL), and the reaction mixture was heated and refluxed overnight under nitrogen protection. After the reaction, saturated sodium chloride solution (20 mL) was added to quench the reaction, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and reduced in pressure. The solvent was evaporated, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain yellow solid compound 12-3 (0.8 g, yield 72%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.24 (dd, J=6.9, 2.0 Hz, 1H), 7.88-7.77 (m, 1H), 7.63-7.51 (m, 2H), 7.45-7.32 (m, 1H), 7.25–7.16 (m, 2H), 3.83 (s, 3H) ppm.

Step 2: Synthesis of Compound 12-5

Compound 12-3 (1.16 g, 7.6 mmol) and compound 12-4 (2.0 g, 8.0 mmol) were dissolved in DMF (30 mL), K ₂ CO ₃ (1.58 g, 11.43 mmol) was added, and the temperature was raised to 140° C. to react overnight . After the reaction, 30 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain compound 12-5 (2.37 g, yield 81.3%) as a yellow oil. MS(ESI, pos.ion) m/z: 380.1[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.17 (t, J=19.4 Hz, 1H), 8.03 (dd, J=7.8, 1.3 Hz, 1H), 7.63 (dd, J=8.7, 2.3 Hz, 1H) ),7.58(td,J=8.2,1.6Hz,1H),7.53–7.48(m,2H),7.33(t,J=7.6Hz,1H),7.16(d,J=8.2Hz,1H),7.00 (d, J=8.7Hz, 2H), 6.88 (d, J=8.7Hz, 1H), 3.87 (d, J=6.6Hz, 3H), 3.80 (s, 3H) ppm.

Step 3: Synthesis of Compound 12-6

Compound 12-5 (2.5 g, 8.9 mmol) was dissolved in glacial acetic acid (60 mL), iron powder (2.0 g, 35.6 mmol) was added thereto, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was poured into water (200 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a white solid compound 12-6 (1.77 g, yield: 62 %).

MS(ESI, pos.ion) m/z: 318.1[M+H] ⁺ ;

¹ H NMR (600 MHz, DMSO-d ₆ ): δ 10.57 (s, 1H), 7.79 (dd, J=7.7, 1.6 Hz, 1H), 7.63 (td, J=8.1, 1.7 Hz, 1H), 7.52 (dd,J=14.9,8.0Hz,2H),7.38(dd,J=8.4,6.0Hz,4H),7.35-7.31(m,1H),7.01(t,J=11.1Hz,2H),3.82- 3.77(m,3H)ppm.

Step 4: Synthesis of Compound 12-7

Compound 12-6 (1.77 g, 5.5 mmol) was added to 30 mL of toluene, phosphorus oxychloride (1 mL, 11 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.28 mL, 2.2 mmol) was slowly added , the temperature of the reaction solution was raised to 110 °C, and the reaction was carried out for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0 °C, 10 mL of water was added to quench the reaction, and then washed twice with 20 mL of water. The organic phase was washed with 20 mL of saturated brine, and then dried over anhydrous sodium sulfate. The organic solvent was removed, and the crude product obtained was directly subjected to the next reaction without further purification.

Sodium hydride (60% dispersed in mineral oil, 0.44 g, 11 mmol) was added to 30 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 5 mL of compound 2-7 (1.27 g, 5.5 mmol) was added After the addition of anhydrous DMF solution, the reaction mixture was heated to 30°C and stirred for two hours. The crude product obtained above was dissolved in 5 ml of anhydrous DMF, and then added to the above reaction solution, and the reaction continued to stir overnight. The reaction was quenched with 10 mL of water at 0°C and washed with 10 mL of ethyl acetate. The pH of the aqueous phase was adjusted to 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 12-7 as a yellow solid (1.48 g, yield 47%).

MS (ESI, pos.ion) m/z: 531.2 [M+H] ⁺ .

Step 5: Synthesis of Compound 12-8

Compound 12-7 (0.7 g, 1.32 mmol), compound 1-9 (0.58 g, 1.45 mmol), EDCI (0.28 g, 1.45 mmol) and HOAT (0.26 g, 1.45 mmol) were added to a round bottom flask under nitrogen Protection, additional 10 mL of dichloromethane was added, then cooled to 0 °C, and finally DIPEA (0.92 mL, 5.28 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 12-8 as a pale yellow solid (0.9 g, yield 92%).

MS(ESI, pos.ion) m/z: 743.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.11 (s, 1H), 7.55-7.49 (m, 4H), 7.41 (s, 1H), 7.32 (dd, J=8.3, 2.1 Hz, 1H), 7.27 –7.19(m,3H),7.14(s,1H),6.97(d,J=8.7Hz,2H),5.90–5.75(m,2H),5.32(d,J=17.0Hz,1H),5.18( d, J＝10.5Hz, 1H), 4.35(s, 1H), 3.87(d, J＝6.3Hz, 4H), 2.97(s, 1H), 2.55(d, J＝7.4Hz, 2H), 2.16– 2.14 (m, 1H), 2.04–1.98 (m, 1H), 1.50 (s, 9H), 1.41–1.31 (m, 2H), 1.07 (d, J=7.8Hz, 2H) ppm.

Step 6: Synthesis of Compound 12-9

Compound 12-8 (0.8 g, 1.1 mmol) was dissolved in 5 mL of ethyl acetate, cooled to 0°C, and then 30% hydrochloric acid in ethyl acetate (15 mL) was added, and the reaction mixture was stirred at room temperature , the reaction ends when there is no gas evolution. After filtration, the obtained white solid was washed with 10 mL of ethyl acetate to obtain compound 12-9, which was directly subjected to the next reaction without further purification.

MS (ESI, pos.ion) m/z: 643.3 [M+H] ⁺ .

Step 7: Synthesis of Compounds 12-10

Compound 12-9 (0.72 g, 1.05 mmol), compound 2-11 (0.52 g, 1.16 mmol), EDCI (0.22 g, 1.16 mmol) and HOAT (0.21 g, 1.16 mmol) were added to a round bottom flask under nitrogen Under protection, 8 mL of dichloromethane was added, then cooled to 0°C, and then DIPEA (0.73 mL, 4.2 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 6 hours. The reaction was quenched with 5 mL of water, then extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain the crude product It was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 12-10 as a pale yellow solid (0.37 g, yield 40%).

MS(ESI, pos.ion) m/z: 896.3 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.26 (s, 1H), 7.51 (d, J=7.3 Hz, 4H), 7.40 (s, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.22(t,J＝8.0Hz,3H),6.98(d,J＝7.5Hz,2H),5.98(s,1H),5.80(td,J＝16.4,6.2Hz,2H),5.34(d,J ＝18.0Hz, 2H), 5.17(d, J＝8.4Hz, 1H), 4.97(dd, J＝23.8, 13.6Hz, 2H), 4.46(s, 1H), 4.36–4.22(m, 1H), 4.01 (d, J＝26.2Hz, 1H), 3.85(d, J＝10.4Hz, 3H), 2.96(s, 1H), 2.55(s, 2H), 2.12(d, J＝20.2Hz, 2H), 2.06 (d, J=5.8Hz, 4H), 1.74 (d, J=11.7Hz, 1H), 1.65 (s, 1H), 1.37 (d, J=20.8Hz, 15H), 1.07 (s, 2H) ppm.

Step 8: Synthesis of Compounds 12-11

Compound 12-10 (0.37 g, 0.41 mmol) was dissolved in 100 mL of 1,2-dichloroethane, 0.03 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 75° C. and stirred for 24 hours . After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a white solid compound 12-11 (0.2 g, Yield: 56%).

MS(ESI, pos.ion) m/z: 868.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.27 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.52 (d, J=8.6 Hz, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.42(d, J＝1.6Hz, 1H), 7.20(t, J＝7.6Hz, 2H), 7.15(t, J＝7.4Hz, 1H), 6.98(d, J＝8.6Hz, 2H), 6.94(s, 1H), 5.96(s, 1H), 5.74(d, J=8.9Hz, 1H), 5.14(d, J=7.3Hz, 1H), 5.02(t, J=9.4Hz, 1H), 4.67–4.53(m, 2H), 4.37(s, 1H), 4.05(d, J=8.4Hz, 1H), 3.86(s, 3H), 2.99–2.88(m, 1H), 2.68(t , J＝10.4Hz, 2H), 2.58(s, 1H), 2.34(d, J＝8.6Hz, 1H), 1.94(d, J＝5.7Hz, 2H), 1.89–1.78(m, 1H), 1.64 (d, J=27.1Hz, 5H), 1.54–1.42 (m, 5H), 1.33 (s, 9H), 1.32-1.31 (m, 1H), 1.17 (dd, J=11.1, 6.0Hz, 1H), 1.14-1.07 (m, 1H), 0.99-0.90 (m, 1H) ppm; HPLC purity 95.36%.

Example 13

synthetic route:

Step 1: Synthesis of Compound 13-3

Compound 13-1 (10 g, 50 mmol) and compound 13-2 (7.6 g, 55 mmol) were dissolved in DMF (200 mL), and K ₂ CO ₃ (10.4 g, 75 mmol) was added thereto, and the reaction mixture was warmed to 110° C. to react overnight. After the reaction, 200 mL of water was added to quench the reaction, then extracted with ethyl acetate (100 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain an orange oily liquid 13-3, which was directly carried out to the next step without purification.

MS(ESI, pos.ion) m/z: 324.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 13-4

Compound 13-3 (1 g, 3.4 mmol) was dissolved in glacial acetic acid (50 mL), iron powder (0.96 g, 17.2 mmol) was added thereto, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filtrate was poured into 100 mL of 1N aqueous hydrochloric acid, a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a yellow solid compound 13-4 (600 mg, step 1 and step 1). 2 The two-step yield is 67%).

Step 3: Synthesis of Compound 13-5

Compound 13-4 (50 mg, 0.19 mmol) was suspended in toluene (20 mL), and POCl ₃ (88 mg, 0.57 mmol) and N,N-dimethylaniline (12 mg, 0.09 mmol) were slowly added under stirring. , the reaction mixture was heated and refluxed for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 13-5 (42 mg, yield 79%) as a pale yellow solid.

MS (ESI, pos.ion) m/z: 280.0 [M+H] ⁺ .

Step 4: Synthesis of Compound 13-6

Compound N-Boc-4-(R)-hydroxyproline (56 mg, 0.24 mmol) was dissolved in DMF (10 mL), and NaH (60%, 25 mg, 0.6 mmol) was added under ice bath. After the addition, the reaction mixture was Warm to room temperature and stir for 2 hours.

Compound 13-5 (67 mg, 0.24 mmol) was dissolved in a small amount of DMF, then the resulting solution was added to the above solution, and the reaction continued to stir for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, the pH value was adjusted to 2-3 with 1N HCl aqueous solution, and then extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) Purification gave compound 13-6 as a pale yellow solid (100 mg, yield 87%).

MS (ESI, pos.ion) m/z: 475.2 [M+H] ⁺ .

Step 5: Synthesis of Compound 13-7

Compound 13-6 (50 mg, 0.11 mmol), compound 1-9 (43 mg, 0.11 mmol), EDCI (22 mg, 0.12 mmol) and HOAT (16 mg, 0.12 mmol) were suspended in CH ₂ Cl ₂ (15 mL) over ice DIPEA (47 mg, 0.36 mmol) was added under the bath and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the pH value was adjusted to 2 with 1N aqueous hydrochloric acid solution, then extracted with dichloromethane (10 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) Purification gave compound 13-7 as a pale yellow solid (68 mg, yield 91%).

MS (ESI, pos.ion) m/z: 687.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 13-9

Compound 13-7 (1.18 g, 1.7 mmol) was dissolved in 5N HCl in EtOAc (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The resulting residue was diluted in CH ₂ Cl ₂ (50 mL), then compound 2-11 (768 mg, 1.7 mmol), EDCI (546 mg, 2.85 mmol) and HOAT (388 mg, 2.85 mmol) were added under ice bath, and then added DIPEA (924 mg, 7.15 mmol) and the resulting reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 13-9 (1.09 g, 2:1) as a pale yellow solid. step yield 76%).

MS (ESI, pos.ion) m/z: 840.3 [M+H] ⁺ .

Step 7: Synthesis of Compounds 13-10

Compound 13-9 (260 mg, 0.31 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 75 °C for 48 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 13-10 (180 mg, yield 72%) as a white solid.

HRMS(ESI, pos.ion) m/z: 812.3 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.61-10.40 (m, 1H), 8.07-7.98 (m, 1H), 7.86-7.76 (m, 2H), 7.60-7.35 (m, 3H), 7.25- 7.15(m, 4H), 5.97(s, 1H), 5.73(d, J=7.7Hz, 1H), 5.36–5.32(m, 1H), 5.00(s, 1H), 4.75–4.69(m, 1H) ,4.55–4.42(m,2H),4.18–4.12(m,1H),2.94(s,1H),2.70–2.56(m,3H),2.37(s,1H),1.94–1.85(m,3H) ,1.61(s,1H),1.46–1.10(m,21H),0.94(s,1H)ppm;

HPLC purity: 95.99%.

Example 14

synthetic route:

Step 1: Synthesis of Compound 14-2

Compound 14-1 (5.0 g, 22 mmol) was added to 100 mL of toluene, phosphorus oxychloride (4 mL, 44 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (1.1 mL, 8.8 mmol) was slowly added, The temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0°C, 50 mL of water was added to quench the reaction, and then washed with water (50 mL×2). The separated organic phase was washed with 50 mL of saturated brine, and then dried with anhydrous sodium sulfate. The organic solvent was removed under reduced pressure to obtain compound 14-2, which was directly subjected to the next reaction without further purification.

Step 2: Synthesis of Compound 14-3

Sodium hydride (60% dispersed in mineral oil, 1.8 g, 45.1 mmol) was added to 100 mL of anhydrous tetrahydrofuran, cooled to 0°C under nitrogen protection, and then 20 mL of compound 2-7 (5.08 g, 22 mmol) was added After the addition of anhydrous tetrahydrofuran solution, the reaction mixture was warmed to 30°C and stirred for two hours. A solution of compound 14-2 (5.4 g, 22 mmol) in 20 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then stirring was continued overnight. After the reaction was completed, the reaction was quenched with 50 mL of water at 0°C and washed with 50 mL of ethyl acetate. The separated aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1), Compound 14-3 (8 g, 82% yield) was obtained as a white solid.

Step 3: Synthesis of Compound 14-4

Compound 14-3 (1.2 g, 2.7 mmol) was dissolved in a mixed solvent of 10 mL of 1,2-dichloroethane, 10 mL of water and 10 mL of acetonitrile, and NaIO ₄ (1.73 g, 8.1 mmol) was added under nitrogen protection and _RuCl3 (0.035 g, 0.03 mmol), the reaction mixture was reacted at 30°C overnight. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (10 mL×3), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain white solid compound 14-4 (0.92 g, yield 72%).

MS(ESI,neg,ion)m/z:471.0[MH] ^- ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.08 (dd, J=19.9, 7.1 Hz, 2H), 7.88-7.68 (m, 3H), 7.58 (t, J=7.4 Hz, 1H), 7.33 (t , J＝7.0Hz, 2H), 5.81(s, 1H), 3.98-3.96(m, 2H), 3.72(d, J＝12.3Hz, 1H), 2.75-2.65(m, 2H), 1.51-1.47( m,9H)ppm.

Step 4: Synthesis of Compound 14-5

Compound 14-4 (0.92 g, 1.9 mmol), compound 1-9 (0.86 g, 2.14 mmol), EDCI (0.45 g, 2.3 mmol) and HOAT (0.29 g, 2.14 mmol) were added to a round bottom flask under nitrogen To protect, add 15 mL of dichloromethane, then cool to 0°C and add DIPEA (1.36 mL, 7.8 mmol). The temperature of the reaction solution was raised to 30°C, and the mixture was stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The combined organic phases were washed with 10 ml of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) Purification gave compound 14-5 as a yellow solid (1.26 g, 95% yield).

MS(ESI,neg,ion)m/z:683.2[MH] ^- ;

Step 5: Synthesis of Compound 14-6

Compound 14-5 (1.2 g, 1.7 mmol) was dissolved in 5 mL of ethyl acetate, cooled to 0°C, and then 30% hydrochloric acid in ethyl acetate (16 mL) was added, and the reaction mixture was stirred at room temperature , the reaction ends when there is no gas evolution. After filtration, the obtained white solid was washed with 10 mL of ethyl acetate to obtain a white compound 14-6, which was directly subjected to the next reaction without further purification.

MS (ESI, pos.ion) m/z: 585.1 [M+H] ⁺ .

Step 6: Synthesis of Compound 14-7

Compound 14-6 (0.73 g, 1.17 mmol), compound 2-11 (0.64 g, 1.41 mmol), EDCI (0.27 g, 1.41 mmol) and HOAT (0.19 g, 1.41 mmol) were added to a round bottom flask under nitrogen To protect, add 10 mL of dichloromethane, then cool to 0°C and add DIPEA (0.82 mL, 4.68 mmol). The temperature of the reaction solution was raised to 30°C, and the mixture was stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1), Compound 14-7 (0.83 g, 86% yield) was obtained as a white solid.

Step 7: Synthesis of Compound 14-8

Compound 14-7 (0.4 g, 0.48 mmol) was dissolved in 100 mL of 1,2-dichloroethane, 0.04 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 65 °C and stirred for 48 hours . After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a white solid compound 14-8 (0.16 g, Yield: 41%).

MS(ESI, pos.ion) m/z: 810.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.35 (s, 1H), 8.03 (d, J=7.3 Hz, 2H), 7.68 (dd, J=13.8, 4.3 Hz, 2H), 7.60-7.49 (m ,1H),7.39(d,J＝7.3Hz,1H),7.31(dd,J＝14.8,7.3Hz,2H),6.09–5.91(m,1H),5.83–5.64(m,1H),5.28( s, 1H), 4.96(m, 1H), 4.76(d, J=11.0Hz, 1H), 4.59(s, 1H), 4.35(d, J=46.0Hz, 1H), 4.08(d, J=9.5 Hz, 1H), 3.00–2.81 (m, 1H), 2.67 (m, 1H), 2.20 (s, 2H), 1.82 (m, 3H), 1.61 (m, 1H), 1.55–1.37 (m, 9H) ,1.37–1.20(m,10H),1.01–0.80(m,4H)ppm;

HPLC purity: 95.41%.

Example 15

synthetic route:

Step 1: Synthesis of Compound 15-1

Compound 6-10 (1.2 g, 2.31 mmol), 4-methoxyphenylboronic acid (0.35 g, 2.31 mmol), Pd(PPh ₃ ) ₄ (223 mg, 0.19 mmol) and K ₂ CO ₃ (1.33 g, 9.56 mmol) was dissolved in a mixed solvent of THF (30 mL) and water (5 mL), and the reaction solution was refluxed overnight under nitrogen protection. After the reaction, saturated sodium chloride solution (100 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1 ) was purified, yellow solid compound 15-1 (1.15 g, yield 91%).

MS (ESI, pos.ion) m/z: 547.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 15-2

Compound 15-1 (1.15 g, 2.1 mmol), compound 1-9 (0.93 g, 2.3 mmol), EDCI (0.52 g, 2.7 mmol) and HOAT (0.31 g, 2.3 mmol) were suspended in CH ₂ Cl ₂ (20 mL) ), DIPEA (0.95 mL, 5.5 mmol) was added under an ice bath, and after the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a pale yellow solid compound 15-2 (1.3 g , the yield is 81%).

MS (ESI, pos.ion) m/z: 759.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 15-3

Compound 15-2 (600 mg, 0.79 mmol) was dissolved in 5N HCl in ethyl acetate (15 mL), and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure. The resulting residue was diluted with CH ₂ Cl ₂ (15 mL), then compound 2-11 (429 mg, 0.95 mmol), EDCI (197 mg, 1.03 mmol) and HOAT (128 mg, 0.95 mmol) were added, and DIPEA ( 0.36 mL, 2.05 mmol), the resulting reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 15-3 (220 mg, yield) as a pale yellow solid. rate 30%).

MS(ESI, pos.ion) m/z: 912.2 [M+H] ⁺ .

Step 4: Synthesis of Compound 15-4

Compound 15-3 (200 mg, 0.22 mmol) was dissolved in 1,2-dichloroethane (200 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 15-4 (70 mg, yield 36%) as a white solid.

HRMS(ESI, pos.ion) m/z: 884.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.69-7.62 (m, 1H), 7.57-7.52 (m, 1H), 7.50-7.44 (m, 3H), 7.32-7.28 (m, 1H), 7.26- 7.15 (m, 2H), 7.11–7.05 (m, 1H), 7.02–6.95 (m, 2H), 5.96 (d, J=2.5Hz, 1H), 5.71 (dd, J=17.6, 8.5Hz, 1H) ,5.31(s,1H),5.10–4.97(m,1H),4.77–4.62(m,1H),4.53(s,1H),4.48–4.38(m,1H),4.11–4.03(m,1H) ,3.86(s,3H),2.92(s,1H),2.71–2.62(m,2H),2.54(s,1H),2.37–2.28(m,1H),1.99–1.81(m,4H),1.64 (s, 2H), 1.42–1.23 (m, 15H), 1.17–1.07 (m, 2H), 0.96–0.88 (m, 2H) ppm;

HPLC purity: 91.6%.

Example 16

synthetic route:

Step 1: Synthesis of Compound 16-1

Compound 4-bromo-2-fluoronitrobenzene (3.30 g, 15 mmol), 4-fluorobenzeneboronic acid (2.74 g, 18 mmol), Pd(PPh ₃ ) ₄ (0.5 g, 0.45 mmol) and K ₂ CO ₃ ( 10.35 g, 75 mmol) was dissolved in a mixed solvent of THF (80 mL) and water (20 mL), and the reaction solution was refluxed overnight under nitrogen protection. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound 16-1 (2.8 g, yield 87%) as a yellow solid.

Step 2: Synthesis of Compound 16-3

Compound 16-1 (1.74 g, 7.4 mmol) and compound 16-2 (1.14 g, 7.4 mmol) were dissolved in DMF (20 mL), and K ₂ CO ₃ (1.12 g, 8.1 mmol) was added thereto, and the reaction mixture was The temperature was raised to 110°C for overnight reaction. After the reaction was completed, 20 mL of water was added to quench the reaction, then the pH value was adjusted to 2-3 with 1N aqueous HCl solution, extracted with ethyl acetate (50 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was evaporated under reduced pressure to obtain compound 16-3 as an orange oily liquid, which was directly carried out to the next step without purification.

Step 3: Synthesis of Compound 16-4

Compound 16-3 was dissolved in glacial acetic acid (100 mL), iron powder (2.1 g, 37 mmol) was added thereto, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the obtained filtrate was poured into water (200 mL), and a solid was precipitated,

After filtration, the filter cake was washed with water and dried to obtain compound 16-4 as a yellow solid (1.5 g, 64% yield in two steps).

Step 4: Synthesis of Compound 16-5

Compound 16-4 (1.4 g, 4.4 mmol) was suspended in toluene (20 mL), POCl ₃ (1.3 g, 8.8 mmol) and N,N-dimethylaniline (0.21 g, 1.8 mmol) were slowly added with stirring, After completion, the reaction solution was heated and refluxed for 3 hours. After completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 16-5 as a pale yellow solid (1.0 g, yield 67%).

Step 5: Synthesis of Compound 16-6

Compound N-Boc-4-(R)-hydroxyproline (0.76 g, 3.29 mmol) was dissolved in DMF (20 mL), NaH (60% dispersed in mineral oil, 0.35 g, 8.94 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. Compound 16-5 (1.0 g, 2.94 mmol) was dissolved in a small amount of DMF, added to the above reaction, and stirring was continued for 12 hours. After the reaction, the reaction solution was poured into 300 mL of water, the pH value was adjusted to 2-3 with 1N HCl aqueous solution, and then extracted with ethyl acetate (50 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the organic solvent was spin-dried under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2 : 1) Purification to obtain compound 16-6 as a pale yellow solid (1.4 g, yield 90%).

MS (ESI, pos.ion) m/z: 535.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 16-7

Compound 16-6 (530 mg, 1.0 mmol), compound 1-9 (442 mg, 1.1 mmol), EDCI (248 mg, 1.3 mmol) and HOAT (150 mg, 1.1 mmol) were suspended in CH ₂ Cl ₂ (15 mL) over ice DIPEA (0.6 mL, 2.6 mmol) was added under the bath. After the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 16-7 (670 mg, yield 90%).

MS (ESI, pos.ion) m/z: 747.2 [M+H] ⁺ .

Step 7: Synthesis of Compound 16-8:

Compound 16-7 (670 mg, 0.90 mmol) was dissolved in 5N HCl in EtOAc (15 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The resulting residue was diluted with CH ₂ Cl ₂ (15 mL), then compound 2-11 (488 mg, 1.08 mmol), EDCI (223 mg, 1.17 mmol) and HOAT (146 mg, 1.08) were added, followed by DIPEA (0.47 mmol) under ice bath mL, 2.70 mmol). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 16-8 (320 mg, yield) as a pale yellow solid. rate 40%).

MS (ESI, pos.ion) m/z: 900.3 [M+H] ⁺ .

Step 8: Synthesis of Compound 16-9

Compound 16-8 (120 mg, 0.13 mmol) was dissolved in 1,2-dichloroethane (150 mL), Grubbs second-generation catalyst (15 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 16-9 (50 mg, yield 44%) as a white solid.

HRMS(ESI, pos.ion) m/z: 872.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.31 (s, 1H), 7.65 (s, 1H), 7.54–7.44 (m, 4H), 7.40 (t, 1H), 7.31–7.27 (m, 2H) ,7.12(t,2H),7.02(s,1H),5.98(s,1H),5.74(dd,J=17.4,8.5Hz,1H),5.23(d,J=7.3Hz,1H),5.01( t, J=9.2Hz, 1H), 4.81–4.49 (m, 2H), 4.41 (t, J=7.5Hz, 1H), 4.16–4.01 (m, 1H), 2.93 (s, 1H), 2.74–2.49 (m, 3H), 2.39–2.29 (m, 1H), 1.99–1.77 (m, 4H), 1.69–1.57 (m, 2H), 1.47–1.28 (m, 15H), 1.17–1.07 (m, 2H) , 0.95-0.89 (m, 2H) ppm; HPLC purity: 94.00%.

Example 17

synthetic route:

Step 1: Synthesis of Compound 17-3

Compound 5-bromo-2-fluoronitrobenzene (1.0 g, 4.5 mmol), 4-fluorobenzeneboronic acid (0.75 g, 5.4 mmol), Pd(PPh ₃ ) ₄ (0.52 g, 0.45 mmol) and K ₂ CO ₃ (1.24 g, 9 mmol) was dissolved in a mixed solvent of THF (24 mL) and water (6 mL), and the reaction mixture was stirred at room temperature overnight under nitrogen protection. After the reaction, saturated sodium chloride solution (20 mL) was added to quench, extracted with ethyl acetate (3×10 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product, which was washed with silica gel Column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) was purified to obtain yellow solid compound 17-3 (0.8 g, yield 76%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.24 (dd, J=6.9, 2.0 Hz, 1H), 7.81 (ddd, J=15.9, 9.7, 6.1 Hz, 1H), 7.56 (dd, J=8.3, 5.3Hz, 2H), 7.44–7.35 (m, 1H), 7.24–7.17 (m, 2H) ppm.

Step 2: Synthesis of Compound 17-5

Compound 17-3 (1.5 g, 6.3 mmol) and compound 17-4 (1.1 g, 6.6 mmol) were dissolved in DMF (30 mL), K ₂ CO ₃ (1.04 g, 7.56 mmol) was added, and the temperature was raised to 140° C. to react overnight . After the reaction, 40 mL of water was added to quench the reaction, extracted with ethyl acetate three times (10 mL×3), the organic phases were combined, the extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The solvent gave yellow solid compound 17-5 (1.9 g, yield 79.3%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.33 (d, J=12.2 Hz, 1H), 7.97 (dd, J=6.8, 1.1 Hz, 1H), 7.65-7.45 (m, 6H), 7.17 (t , J=8.5Hz, 2H), 7.11 (d, J=8.4Hz, 1H), 3.85 (d, J=5.9Hz, 3H) ppm.

Step 3: Synthesis of Compound 17-6

Compound 17-5 (1.9 g, 4.9 mmol) was dissolved in glacial acetic acid (50 mL), iron powder (1.1 g, 19.6 mmol) was added, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was poured into water (200 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain compound 17-6 as a white solid.

Step 4: Synthesis of Compound 17-7

Compound 17-6 (0.9 g, 2.8 mmol) was added to 15 mL of toluene, phosphorus oxychloride (0.5 mL, 5.6 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.14 mL, 1.12 mmol) was slowly added mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0°C, 10 mL of water was added to quench the reaction, and then washed with (20 mL × 2). The organic phase was washed with 20 mL of saturated brine, and then dried over anhydrous sodium sulfate and reduced under reduced pressure. The organic solvent was removed under low temperature, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain 600 mg of an intermediate product.

Sodium hydride (0.17 g, 4.4 mmol, 60% dispersed in mineral oil) was added to 10 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 2 of compound 2-7 (0.5 g, 2.2 mmol) was added. mL of anhydrous DMF solution, then warmed to 30°C and stirred for two hours. The intermediate product obtained above was dissolved in 2 ml of anhydrous DMF, added to the reaction solution, and then reacted overnight. At 0°C, the reaction was quenched with 10 mL of water, washed with 10 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined and washed with saturated brine , dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a yellow oily compound 17-7 ( 0.4 g, 23% yield).

MS (ESI, pos.ion) m/z: 535.1 [M+H] ⁺ .

Step 5: Synthesis of Compounds 17-8

Compound 17-7 (0.35 g, 0.65 mmol), compound 1-9 (0.29 g, 0.72 mmol), EDCI (0.14 g, 0.72 mmol) and HOAT (0.13 g, 0.72 mmol) were added to a round bottom flask under nitrogen To protect, add 5 mL of dichloromethane, then cool to 0°C and add DIPEA (0.45 mL, 2.8 mmol). The temperature of the reaction solution was raised to 30°C, and the mixture was stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain a crude product It was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 17-8 (0.34 g, yield 70%).

MS(ESI, pos.ion) m/z: 747.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.06 (d, J=29.7 Hz, 1H), 7.53 (dd, J=6.6, 4.7 Hz, 4H), 7.46 (d, J=7.3 Hz, 1H), 7.42-7.35(m, 2H), 7.28(s, 2H), 7.12(t, J=8.6Hz, 2H), 5.88(s, 1H), 5.86-5.73(m, 1H), 5.33(d, J= 16.9Hz, 1H), 5.18(d, J=10.5Hz, 1H), 4.37(s, 1H), 3.95(t, J=10.6Hz, 2H), 2.97(s, 1H), 2.58(d, J= 22.2Hz, 2H), 2.22–2.11 (m, 1H), 2.01 (dd, J=14.3, 7.0Hz, 1H), 1.54–1.41 (m, 9H), 1.40–1.31 (m, 3H), 1.03 (d , J=24.4Hz, 2H)ppm.

Step 6: Synthesis of Compounds 17-9

Compound 17-8 (0.63 g, 0.84 mmol) was dissolved in 5 mL of ethyl acetate, cooled to 0°C, then 15 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until The reaction was terminated when no gas evolved. After filtration, the obtained white solid was washed with 10 mL of ethyl acetate, and the obtained solid was directly subjected to the next reaction without further purification.

Step 7: Synthesis of Compounds 17-10

Compound 17-9 (0.57 g, 0.84 mmol), compound 2-11 (0.42 g, 0.92 mmol), EDCI (0.18 g, 0.92 mmol) and HOAT (0.16 g, 0.92 mmol) were added to a round bottom flask under nitrogen To protect, add 10 mL of dichloromethane, then cool to 0°C and add DIPEA (0.58 mL, 3.34 mmol). The temperature of the reaction solution was raised to 30°C, and the mixture was stirred for 6 hours. After the reaction was completed, the reaction was quenched with 5 mL of water and 4 mL of 1N aqueous hydrochloric acid, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and then reduced The organic solvent was removed under pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 17-10 (0.37 g, yield 49%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.24 (s, 1H), 7.51-7.56 (m, 4H), 7.44 (t, J=7.3 Hz, 1H), 7.38-7.30 (m, 2H), 7.30 –7.22(m,2H),7.12(t,J=8.6Hz,2H),5.97(s,1H),5.90–5.72(m,2H),5.37(d,J=8.5Hz,1H),5.30( d, J＝17.2Hz, 1H), 5.17 (d, J＝10.9Hz, 1H), 4.97 (dd, J＝21.8, 13.6Hz, 2H), 4.49 (d, J＝8.2Hz, 2H), 4.35– 4.22(m, 1H), 4.04(d, J=8.1Hz, 1H), 2.91–3.01(m, 1H), 2.61(d, J=6.7Hz, 1H), 2.54(s, 1H), 2.15(dd , J=17.4, 8.5Hz, 1H), 2.04 (d, J=6.7Hz, 4H), 1.73 (d, J=8.4Hz, 2H), 1.69–1.57 (m, 2H), 1.39 (s, 15H) , 1.07(d, J=7.8Hz, 2H).

Step 8: Synthesis of Compounds 17-11

Compound 17-10 (0.37 g, 0.41 mmol) was dissolved in 100 mL of 1,2-dichloroethane, 0.03 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 75° C. and stirred for 24 hours . After cooling to room temperature, the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 17-11 (0.25 g, yield: 70 %).

MS(ESI, pos.ion) m/z: 872.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.28 (s, 1H), 7.63 (s, 1H), 7.53–7.42 (m, 4H), 7.41 (t, 1H), 7.32–7.25 (m, 2H) ,7.10(t,2H),7.08(s,1H),5.98(s,1H),5.75(m,1H),5.23(d,J＝7.3Hz,1H),5.01(t,J＝9.2Hz, 1H), 4.81-4.49(m, 2H), 4.43(t, J=7.5Hz, 1H), 4.16-4.01(m, 1H), 2.93(s, 1H), 2.74-2.49(m, 3H), 2.41 –2.31(m,1H),1.97–1.73(m,4H),1.71–1.57(m,2H),1.47–1.28(m,15H),1.16–1.04(m,2H),0.92–0.86(m, 2H)ppm;

HPLC purity: 90.36%.

Example 18

synthetic route

Step 1: Synthesis of Compound 18-2

Compound 11-4 (1.23 g, 5 mmol) and compound 18-1 (0.85 g, 5 mmol) were dissolved in DMF (20 mL), K ₂ CO ₃ (0.83 g, 6 mmol) was added, and the reaction mixture was warmed to 110° C. and reacted overnight. After the reaction was completed, the reaction solution was quenched by adding water, adjusted to pH 2-3 with 1N HCl aqueous solution, and then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution, and anhydrous It was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain an orange oily liquid 18-2, which was directly carried out to the next step without purification.

MS (ESI, pos.ion) m/z: 398.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 18-3

The crude compound 18-2 was dissolved in glacial acetic acid (100 mL), iron powder (1.4 g, 25 mmol) was added, and the reaction mixture was heated to 110° C. for 4 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was poured into water (200 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a yellow solid compound 18-3 (1.5 g, two-step yield 94 %).

MS (ESI, pos.ion) m/z: 336.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 18-4

Compound 18-3 (1.5 g, 4.47 mmol) was suspended in toluene (20 mL), POCl ₃ (1.37 g, 8.94 mmol) and N,N-dimethylaniline (0.22 g, 1.79 mmol) were slowly added with stirring, After the addition, the reaction solution was heated and refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 18-4 as a pale yellow solid (1.5 g, yield 95%).

Step 4: Synthesis of Compound 18-5

The compound N-Boc-4-(R)-hydroxyproline (1.18 g, 5.1 mmol) was dissolved in DMF (20 mL), and NaH (60% dispersed in mineral oil, 0.4 g, 10.2 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes.

Compound 18-4 (1.5 g, 4.2 mmol) was dissolved in a small amount of DMF, then added to the above reaction and stirring was continued for 12 hours. After the reaction, the reaction solution was poured into 300 mL of water, and the pH value was adjusted to 2-3 with 1N HCl aqueous solution, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution, Dry over anhydrous sodium sulfate, filter, remove the organic solvent under reduced pressure, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 18-5 as a pale yellow solid (900 mg, 39% yield).

MS (ESI, neg.ion) m/z: 547.1 [MH] ^- .

Step 5: Synthesis of Compound 18-6

Compound 18-5 (900 mg, 1.64 mmol), compound 1-9 (791 mg, 1.97 mmol), EDCI (407 mg, 2.13 mmol) and HOAT (266 mg, 1.97 mmol) were suspended in CH ₂ Cl ₂ (30 mL), ice bath DIPEA (0.85 mL, 4.92 mmol) was added at the bottom, and after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was spun off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 18-6 (1.1 g , the yield is 88%).

MS (ESI, pos.ion) m/z: 761.0 [M+H] ⁺ .

Step 6: Synthesis of Compound 18-7

Compound 18-6 (1.1 g, 1.45 mmol) was dissolved in 5N HCl in ethyl acetate solution (20 mL), and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue was diluted with CH ₂ Cl ₂ (40 mL), then compound 2-11 (716 g, 1.58 mmol), EDCI (328 mg, 1.72 mmol) and HOAT (214 mg, 1.58 mmol) were added, and DIPEA (0.7 mL) was added under ice bath. , 3.96 mmol), after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 18-7 (500 mg, yield) as a pale yellow solid. rate 38%).

MS (ESI, neg.ion) m/z: 912.2 [MH] ^- .

Step 7: Synthesis of Compounds 18-8

Compound 18-7 (480 mg, 0.52 mmol) was dissolved in 1,2-dichloroethane (500 mL), Grubbs second-generation catalyst (50 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by preparative HPLC to obtain compound 18-8 (200 mg, yield 43%) as a white solid.

HRMS(ESI, pos.ion) m/z: 886.4[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.31 (s, 1H), 7.60–7.49 (m, 3H), 7.41–7.33 (m, 2H), 7.28–7.22 (m, 1H), 7.02–6.95 ( m, 3H), 6.86(s, 1H), 5.94(s, 1H), 5.74(d, J=8.3Hz, 1H), 5.17(s, 1H), 5.02(t, J=9.1Hz, 1H), 4.78–4.47 (m, 2H), 4.35 (t, J=7.2Hz, 1H), 4.04 (d, J=8.5Hz, 1H), 3.87 (s, 3H), 2.98–2.86 (m, 1H), 2.76 –2.52(m,3H), 2.43–2.28(m,1H), 1.99–1.71(m,5H), 1.68–1.56(m,1H), 1.44–1.28(m,15H), 1.17–1.07(m, 2H),0.98–0.88(m,2H)ppm;

HPLC purity 94.64%.

Example 19

synthetic route:

Step 1: Synthesis of Compound 19-3

Compound 19-1 (5 g, 33 mmol) and compound 19-2 (5.5 g, 35 mmol) were dissolved in DMF (100 mL), K ₂ CO ₃ (6.8 g, 50 mmol) was added, and the reaction mixture was heated to 60° C. for 3 hours . After the reaction, 100 mL of water was added to quench the reaction, then extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. solvent to obtain compound 19-3 as an orange oily liquid, which was directly carried out to the next step without purification.

MS (ESI, pos.ion) m/z: 292.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 19-4

The crude product 19-3 (50 mg, 0.17 mmol) was dissolved in glacial acetic acid (10 mL), iron powder (48 mg, 0.86 mmol) was added, and the reaction mixture was heated to 110° C. for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and then the filtrate was poured into 1N aqueous hydrochloric acid (30 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a yellow solid compound 19-4 (27 mg, step 1). and step 2 two-step yield 70%)

Step 3: Synthesis of Compound 19-5

Compound 19-4 (500 mg, 0.22 mmol) was suspended in toluene (50 mL), and POCl ₃ (1 g, 6.5 mmol) and N,N-dimethylaniline (133 mg, 1.1 mmol) were slowly added under stirring. , the reaction solution was heated and refluxed for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 19-5 as a pale yellow solid (44 mg, yield 82%).

MS(ESI, pos.ion) m/z: 248.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 19-6

Compound N-Boc-4-(R)-hydroxyproline (224 mg, 0.97 mmol) was dissolved in DMF (50 mL), NaH (60% dispersed in mineral oil, 78 mg, 3.2 mmol) was added under ice bath, After completion, the reaction mixture was warmed to room temperature and stirred for 2 hours.

Intermediate 19-5 (200 mg, 0.81 mmol) was dissolved in a small amount of DMF, added to the above solution, and stirring was continued for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, and the pH value was adjusted to 2-3 with 1N HCl aqueous solution, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution, It was dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 19-6 (397 mg) as a pale yellow solid. , the yield is 93%).

MS (ESI, neg.ion) m/z: 441.2 [MH] ^- .

Step 5: Synthesis of Compound 19-7

Compound 19-6 (350 mg, 0.79 mmol), compound 1-9 (318 mg, 0.79 mmol), EDCI (227 mg, 1.19 mmol) and HOAT (161 mg, 1.19 mmol) were suspended in CH ₂ Cl ₂ (50 mL) over ice DIPEA (306 mg, 2.37 mmol) was added under the bath. After the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, adjust the pH value to about 2 with 1N aqueous hydrochloric acid solution, then extract with dichloromethane (20ml×3), combine the organic phases, wash the organic phases with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, reduce The solvent was spun dry, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 19-7 as a pale yellow solid (457 mg, yield 87%). MS (ESI, pos.ion) m/z: 655.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 19-8

Compound 19-7 (480 mg, 0.73 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue was diluted with CH ₂ Cl ₂ (50 mL), then compound 2-11 (322 mg, 0.71 mmol), EDCI (204 mg, 1.07 mmol) and HOAT (146 mg, 1.07 mmol) were added, and DIPEA (275 mg, 1.07 mmol) was added under ice bath. 2.13 mmol), after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 19-8 (484 mg, two steps) as a light yellow solid yield 82%).

Step 7: Synthesis of Compounds 19-9

Compound 19-8 (200 mg, 0.25 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 75 °C for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 19-9 (150 mg, yield 78%) as a white solid.

HRMS (ESI, pos.ion) m/z: 780.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.33 (s, 1H), 7.51 (d, J=48.0 Hz, 2H), 7.14 (d, J=33.4 Hz, 3H), 6.89 (s, 2H), 5.89(s, 1H), 5.72(s, 1H), 5.27(s, 1H), 5.00(s, 1H), 4.62(t, J＝38.8Hz, 2H), 4.36(s, 1H), 4.03(s ,1H),2.92(s,1H),2.62(d,J=26.2Hz,3H),2.35(s,1H),1.87(m,2H),1.59(s,1H),1.38(d,J= 82.9Hz, 18H), 1.12 (d, J=30.7Hz, 2H), 0.93 (s, 2H) ppm;

HPLC purity: 98.29%.

Example 20

synthetic route:

Step 1: Synthesis of Compound 20-1

Compound 6-10 (520 mg, 1.0 mmol), 4-fluorophenylboronic acid (140 mg, 1.0 mmol), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) and K ₂ CO ₃ (690 mg, 5 mmol) were dissolved in THF ( 30 mL) and water (5 mL), the reaction mixture was refluxed overnight under nitrogen protection. After the reaction, saturated sodium chloride solution (100 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then reduced The organic solvent was spun dry, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain yellow solid compound 20-1 (500 mg, yield 93%).

MS (ESI, pos.ion) m/z: 535.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 20-2

Compound 20-1 (500 mg, 0.94 mmol), compound 1-9 (415 mg, 1.03 mmol), EDCI (233 mg, 1.22 mmol) and HOAT (140 mg, 1.03 mmol) were suspended in CH ₂ Cl ₂ (15 mL) over ice DIPEA (0.43 mL, 2.44 mmol) was added under the bath. After the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, 5 mL of 1N aqueous hydrochloric acid was added to quench the reaction, then extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. organic solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 20-2 as a pale yellow solid (520 mg, yield 74%).

MS (ESI, pos.ion) m/z: 747.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 20-3

Compound 20-2 (520 mg, 0.69 mmol) was dissolved in 5N HCl in EtOAc (15 mL) and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue was diluted with CH ₂ Cl ₂ (15 mL), then compound 2-11 (375 mg, 0.83 mmol), EDCI (171 mg, 0.9 mmol) and HOAT (102 mg, 0.76 mmol) were added, and DIPEA (0.36 mL) was added under ice bath. , 2.0 mmol), after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, 1N aqueous hydrochloric acid was added to quench the reaction, then extracted with ethyl acetate (3×20 mL), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure , the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 20-3 as a light yellow solid (370 mg, yield 59%).

MS(ESI, pos.ion) m/z: 900.0 [M+H] ⁺ .

Step 4: Synthesis of Compound 20-4

Compound 20-3 (300 mg, 0.33 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 65° C. for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 20-4 (100 mg, yield 35%) as a white solid.

HRMS(ESI, pos.ion) m/z: 872.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.34 (s, 1H), 7.65 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.53-7.42 (m, 4H), 7.33-7.29 (m, 1H), 7.23 (d, J=7.5Hz, 1H), 7.16–7.08 (m, 3H), 5.97 (s, 1H), 5.73 (dd, J=17.7, 8.6Hz, 1H), 5.30 ( d, J=7.2Hz, 1H), 5.00(t, J=9.3Hz, 1H), 4.86-4.48(m, 2H), 4.41(s, 1H), 4.14-4.03(m, 1H), 2.93(s) ,1H),2.74–2.49(m,3H),2.40–2.28(m,1H),2.00–1.79(m,4H),1.77–1.55(m,2H),1.40–1.21(m,15H),1.18 -1.08(m,2H),0.98-0.88(m,2H)ppm.

Example 21

synthetic route:

Step 1: Synthesis of Compound 21-2

Under ice bath, compound 4-bromo-2-fluorobenzaldehyde (6.0 g, 10.5 mmol) was added to 50 mL of CH ₃ CN, followed by adding NaH ₂ PO ₄ (690 mg, 5.7 mmol) aqueous solution (10 mL), H _{2 O2} (4.71 g, 42 mmol) and NaClO2 (3.78 _g , 42 mmol), the reaction mixture was stirred at room temperature overnight. Water was added to quench the reaction, and a solid was precipitated, which was filtered to obtain a white solid, which was washed with water to obtain compound 21-2 as a white solid (6.8 g, yield: 54%).

MS (ESI, neg.ion) m/z: 217.0 [MH] ^- .

Step 2: Synthesis of Compound 21-3

5 mL of SOCl ₂ was added to the round-bottomed flask, and then compound 21-2 (2.5 g, 11.5 mmol) was added, and the reaction solution was stirred at 75° C. under reflux for about 2 hours. After the reaction of the raw materials, the solvent was evaporated to dryness under reduced pressure, the obtained yellow liquid residue was dissolved in 20 mL of dry THF, and added to 2-amino-4-fluorophenol (1.46 g, 11.5 mmol) and Et ₃ N ( 3.25 mL, 23.0 mmol) in 25 mL of THF, the reaction mixture was warmed to room temperature and reacted overnight. After the reaction, 100 mL of water was added to quench the reaction, adjusted to pH=7 with 1N aqueous hydrochloric acid solution, extracted with dichloromethane (100 mL×3), the organic phases were combined, the organic phases were washed with saturated brine, and dried over anhydrous sodium sulfate, The solvent was spin-dried, and the obtained product 21-3 was directly subjected to the next reaction without further purification.

MS (ESI, pos.ion) m/z: 328.9 [M+H] ⁺ .

Step 3: Synthesis of Compound 21-4

Compound 21-3 (8.5 g, 25.8 mmol), NaOH (1.03 g, 25.8 mmol) and 60 mL of DMF were sequentially added to a 100 mL round-bottomed flask, and the reaction mixture was stirred at reflux overnight. After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into 100 mL of ice water to precipitate a precipitate, filtered, and washed with 20 mL of 1N NaOH aqueous solution and 20 mL of water in turn. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 21-4 (4.1 g, yield: 51%) as a white solid.

MS(ESI, pos.ion) m/z: 307.9[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.71 (s, 1H), 7.71 (dd, J=5.1, 3.2 Hz, 2H), 7.56 (dd, J=8.4, 1.8 Hz, 1H), 7.43 (dd , J = 8.9, 5.4 Hz, 1H), 7.06–6.93 (m, 2H) ppm.

Step 4: Synthesis of Compounds 21-5

In a 100 mL round-bottomed flask, 30 mL of toluene was added, and compound 21-4 (532 mg, 1.73 mmol), POCl ₃ (180 uL, 1.90 mmol) and N,N-dimethylaniline (85 uL, 0.692 mmol) were sequentially added under nitrogen protection, Stir at reflux overnight. After cooling to room temperature, 10 mL of water was added to quench the reaction, extracted with dichloromethane (50 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure to obtain the crude product 21-5, which was not needed. Further purification was carried out directly to the next reaction.

Step 5: Synthesis of Compounds 21-6

NaH (60% dispersed in mineral oil, 0.53 g, 13 mmol) was added to a 100 mL round-bottomed flask, 50 mL of anhydrous DMF was added under nitrogen protection, cooled in an ice bath, and then added containing (2S,4S)-1-( tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.5 g, 6.5 mmol, 1.0 eq) in tetrahydrofuran, (20 mL). The reaction mixture was warmed to room temperature and stirred until no bubbles were formed, then 20 mL of THF solution containing 21-5 (2.2 g, 6.5 mmol) was added, and stirring was continued at room temperature overnight. After the reaction, 10 mL of water was added to quench the reaction, the pH was adjusted to <7 with 1N aqueous hydrochloric acid solution, and then extracted with dichloromethane (50 mL×3), the organic phases were combined, the organic phases were dried over anhydrous magnesium sulfate, filtered, and spin-dried under reduced pressure. Organic solvent, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain 21-6 as a white solid (2.4 g, yield: 71%).

MS(ESI,neg.ion)m/z:519.0[MH] ^-

Step 6: Synthesis of Compounds 21-7

Compound 21-6 (802 mg, 1.54 mmol), 1-9 (620 mg, 1.54 mmol), EDCI (310 mg, 1.62 mmol), HOAT (240 mg, 1.69 mmol) were successively added to a 100 mL round bottom flask, and added under nitrogen protection 10 mL of dichloromethane was cooled in an ice bath, compound DIPEA (0.660 mL, 3.85 mmol) was added at 0° C., and the reaction solution was stirred at room temperature overnight. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, extracted with dichloromethane (50 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried, and the crude product was subjected to silica gel column chromatography (Petroleum ether:ethyl acetate (V:V)=2:1) purification gave 21-7 as a white solid (607 mg, yield: 51%).

MS(ESI, pos.ion) m/z: 733.1[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.07 (s, 1H), 7.57-7.49 (m, 1H), 7.39 (d, J=15.7 Hz, 2H), 7.23 (dd, J=15.0, 7.7 Hz ,1H),7.17–7.08(m,2H),6.91(m,1H),6.87–6.79(m,1H),5.86–5.78(m,1H),5.74(s,1H),5.37–5.27(m ,1H),5.19(d,J＝10.4Hz,1H),4.39-4.27(m,1H),3.94-3.71(m,2H),2.97(s,1H),2.54(s,2H),1.49( s, 9H), 1.42–1.32 (m, 2H), 1.28 (t, J=7.1 Hz, 2H), 1.07 (d, J=7.5 Hz, 2H) ppm.

Step 7: Synthesis of Compounds 21-8

Compound 21-7 (719 mg, 0.98 mmol) and 50 mL of 5N HCl in ethyl acetate were added to a 100 mL round bottom flask, and the reaction solution was stirred at room temperature for 2 hours. A white solid was precipitated, which was filtered, and the obtained solid was washed with ethyl acetate, and then dried in vacuo to obtain a white solid compound 21-8 (591 mg, yield: 90%).

Step 8: Synthesis of Compounds 21-9

Compound 21-8 (502 mg, 0.75 mmol), compound 2-11 (406 mg, 0.90 mmol), EDCI (190 mg, 1.0 mmol), HOAT (115 mg, 0.85 mmol) were added to a 25 mL round-bottomed flask, and added under nitrogen protection 10 mL of DCM was cooled in an ice bath, and compound DIPEA (350 ul, 2.0 mmol) was added at 0 °C. The reaction solution was warmed to room temperature and stirred overnight. After the reaction, 1N aqueous hydrochloric acid was added to quench the reaction, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried. The crude product was used Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) gave Compound 21-9 as a white solid (253 mg, yield: 38%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.20 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.37-7.31 (m, 1H), 7.11 (dd, J=8.5, 5.3 Hz ,1H),7.01(s,1H),6.91(dd,J=9.2,2.8Hz,1H),6.85(dd,J=11.9,4.3Hz,1H),5.89(s,1H),5.87–5.76( m, 2H), 5.31 (t, J=12.8Hz, 1H), 5.18 (d, J=10.4Hz, 1H), 4.98 (dd, J=35.4, 13.6Hz, 2H), 4.50–4.36 (m, 2H) ),4.27(d,J＝11.8Hz,1H),4.00(dd,J＝11.3,3.9Hz,1H),3.00-2.89(m,1H),2.64-2.49(m,2H),2.17-2.09( m, 1H), 2.06 (d, J=5.9Hz, 2H), 1.73 (s, 1H), 1.51 (d, J=9.4Hz, 1H), 1.49–1.44 (m, 3H), 1.44–1.36 (m , 9H), 1.29 (d, J=18.0 Hz, 4H), 1.13 (s, 1H), 1.08 (d, J=7.0 Hz, 2H), 0.93–0.83 (m, 2H) ppm.

Step 9: Synthesis of Compounds 21-10

Compound 21-9 (200 mg, 0.022 mmol), Grubbs second-generation catalyst (50 mg, 0.08 mmol) were added to a 250 mL round-bottomed flask, and then 250 mL of 1,2-dichloroethane was added to dissolve, under nitrogen protection, the reaction solution The temperature was raised to 65°C and stirred for 48 hours. After the reaction was completed, it was cooled to room temperature, the organic solvent was spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid 21-10 (130 mg, Yield: 65%).

MS(ESI, pos.ion) m/z: 858.2[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.31 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 7.09 (dd, J=8.7, 5.2 Hz, 1H ),7.02(s,1H),6.94(d,J＝6.8Hz,1H),6.83(dd,J＝10.5,5.1Hz,1H),5.89(s,1H),5.73(dd,J＝17.4, 8.7Hz, 1H), 5.16 (d, J=7.4Hz, 1H), 5.07–4.96 (m, 1H), 4.66–4.60 (m, 1H), 4.38–4.26 (m, 1H), 4.06–3.94 (m ,1H),2.92(s,1H),2.62(s,1H),2.32(dd,J=16.7,8.2Hz,1H),2.00–1.87(m,2H),1.87–1.78(m,1H), 1.73(s,2H),1.59(dd,J=32.6,19.3Hz,2H),1.54–1.46(m,4H),1.36–1.28(m,9H),1.19–1.07(m,2H),1.05– 0.82(m,4H)ppm;

HPLC purity: 98.98%.

Example 22

synthetic route:

Step 1: Synthesis of Compound 22-2

Compound 21-4 (3.0 g, 9.75 mmol), 4-fluorophenylboronic acid 22-1 (1.4 g, 9.75 mmol), Pd(PPh ₃ ) ₄ (1.0 g, 0.975 mmol) and K ₂ were added to a round-bottomed flask _CO3 (6.7 g, 48.75 mmol), then 90 mL of THF and 30 mL of _H2O were added. Under nitrogen protection, the reaction mixture was warmed to reflux and reacted for 14 hours. After the reaction was completed, it was cooled to room temperature, quenched with 100 mL of water, extracted with ethyl acetate (50 mL×3), the organic phases were combined, rinsed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and spin-dried under reduced pressure. Solvent, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain white solid compound 22-2 (1.5 g, yield: 48%).

MS(ESI, pos.ion) m/z: 324.0[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.63 (s, 1H), 7.91-7.77 (m, 3H), 7.70 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.47-7.40 (m, 1H), 7.35 (t, J=8.5 Hz, 2H), 6.99 (d, J=9.4 Hz, 2H) ppm.

Step 2: Synthesis of Compound 22-3

In a 100 mL round-bottom flask, compound 22-2 (558 mg, 1.73 mmol), POCl ₃ (180 uL, 1.90 mmol), N,N-dimethylaniline (85 uL, 0.692 mmol) were dissolved in 30 mL of toluene, and the reaction solution was refluxed Stir overnight. After the reaction, it was cooled to room temperature, 10 mL of water was added to quench the reaction, extracted with dichloromethane (50 mL×3), the organic phases were combined, rinsed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried, The crude product 22-3 was obtained, and the next reaction was carried out directly without further purification.

Step 3: Synthesis of Compound 22-4

NaH (0.52 g, 13 mmol, 60% dispersed in mineral oil) was added to a 100 mL round-bottomed flask, 50 mL of THF was added under nitrogen protection, cooled in an ice bath, and then compound 2-7 (2.2 g, 6.5 mmol) was added to react. The mixture was warmed to room temperature and stirred until no bubbles were formed, a THF solution (20 mL) containing compound 22-3 (2.2 g, 6.5 mmol) was added, and stirring was continued at room temperature overnight. After the reaction, add water to quench the reaction, adjust pH<7 with dilute hydrochloric acid solution, then extract with dichloromethane (50mL×3), combine the organic phases, rinse with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, spin The organic solvent was dried, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid 22-4 (1.4 g, yield: 62%).

MS(ESI, pos.ion) m/z: 537.2[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.63-7.55 (m, 3H), 7.40 (dd, J=11.6, 3.5 Hz, 2H), 7.21-7.11 (m, 3H), 6.92 (dd, J= 8.3, 6.4Hz, 1H), 6.87–6.79 (m, 1H), 5.76 (d, J=3.3Hz, 1H), 4.65 (t, J=7.7Hz, 1H), 4.53 (t, J=7.8Hz, 1H), 3.97(dt, J＝12.2, 8.2Hz, 1H), 3.88(s, 1H), 2.86-2.74(m, 1H), 2.55-2.41(m, 1H), 1.50(d, J＝17.9Hz ,9H)ppm.

Step 4: Synthesis of Compound 22-5

Compound 22-4 (827 mg, 1.54 mmol), compound 1-9 (620 mg, 1.54 mmol), EDCI (310 mg, 1.62 mmol) and HOAT (240 mg, 1.69 mmol) were added to a 100 mL round bottom flask, and added under nitrogen protection 10 mL of dichloromethane was cooled in an ice bath, compound DIPEA (660 uL, 3.85 mmol) was added at 0° C., and the reaction solution was warmed to room temperature and stirred overnight. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, and extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and spin-dried under reduced pressure. Organic solvent, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 22-5 as a white solid (607 mg, yield: 51%).

MS(ESI, pos.ion) m/z: 749.2[M+H] ⁺ ;

Step 5: Synthesis of Compound 22-6

Compound 22-5 (734 mg, 0.98 mmol) and 30 mL of 5N HCl in ethyl acetate were added to a 100 mL round bottom flask, and the reaction solution was stirred at room temperature for 2 hours. A white solid was produced during the reaction, which was filtered, rinsed with ethyl acetate, and dried to obtain a white solid 22-6 (604 mg, yield: 90%).

Step 6: Synthesis of Compound 22-7

Compound 22-6 (514 mg, 0.75 mmol), compound 2-11 (406 mg, 0.90 mmol), EDCI (190 mg, 1.0 mmol), HOAT (115 mg, 0.85 mmol) were added to a 100 mL round-bottomed flask, and added under nitrogen protection 10 mL of DCM was cooled in an ice bath, compound DIPEA (350 uL, 2.0 mmol) was added at 0°C, and the reaction solution was warmed to room temperature and stirred overnight. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure, and the crude product was used Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) gave 22-7 as a white solid (358 mg, yield: 53%).

Step 10: Synthesis of Compound 22-8

Compound 22-7 (406 mg, 0.45 mmol), Grubbs second-generation catalyst (50 mg, 0.08 mmol) and 1,2-dichloroethane (150 mL) were added to a 250 mL round bottom flask, and the reaction mixture was under nitrogen protection and 65 Stir at °C for 48 hours. After the reaction was completed, it was cooled to room temperature, the organic solvent was spin-dried, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid 22-8 (270 mg, yield : 31%).

MS(ESI, pos.ion) m/z: 874.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.34 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.58-7.46 (m, 3H), 7.34 (s, 1H), 7.32 (d , J=1.6Hz, 1H), 7.30 (d, J=1.6Hz, 1H), 7.16 (t, J=8.5Hz, 3H), 7.13–7.09 (m, 1H), 6.99–6.92 (m, 1H) ,6.82(dd,J＝10.7,5.4Hz,1H),5.92(s,1H),5.73(dd,J＝18.0,8.5Hz,1H),5.24(d,J＝7.5Hz,1H),5.07– 4.94 (m, 1H), 4.74–4.51 (m, 2H), 4.44–4.31 (m, 2H), 4.21–3.98 (m, 1H), 2.92 (d, J=4.7Hz, 1H), 2.74–2.33 ( m,4H),1.87-1.60(m,6H),1.60-1.28(m,12H),1.20-1.05(m,2H),1.04-0.89(m,2H)ppm;

HPLC purity: 94.74%.

Example 23

synthetic route:

Step 1: Synthesis of Compound 23-2

Under ice bath, compound 4-bromo-2-fluorobenzaldehyde (6.0g, 10.5mmol) was added to 50mL CH ₃ CN, then 10mL NaH ₂ PO ₄ (690mg, 5.7mmol) aqueous solution, H ₂ O ₂ were added successively (4.71 g, 42 mmol) and NaClO ₂ (3.78 g, 42 mmol) and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, water was added to quench the reaction, and then a solid was precipitated, which was filtered to obtain a white solid, and the filter cake was washed with water to obtain a white solid compound 23-2 (6.8 g, yield: 54%).

MS (ESI, pos.ion) m/z: 219.0 [M+H] ⁺ .

Step 2: Synthesis of Compound 23-3

Compound 23-2 (2.5 g, 11.5 mmol) and 5 mL of SOCl ₂ were added to a round-bottomed flask, and the reaction mixture was heated to 75° C. and stirred under reflux for 2 hours. After the reaction of the raw materials, the solvent was evaporated to dryness, and the obtained pale yellow liquid residue was dissolved in 20 mL of anhydrous THF, and added to the mixture containing 2-aminophenol (1.46 g, 11.5 mmol), Et ₃ N (3.25 mL under ice bath) , 23.0 mmol) in 25 mL of THF solution, the reaction mixture was warmed to room temperature and reacted overnight. After the reaction is complete, add 100 mL of water to quench the reaction, adjust pH=7 with dilute hydrochloric acid solution, extract with ethyl acetate

(20 mL×3), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure, and the obtained crude product was directly subjected to the next reaction without further purification.

Step 3: Synthesis of Compound 23-4

In a 100 mL round-bottomed flask, compound 23-3 (8 g, 25.8 mmol) and NaOH (1.03 g, 25.8 mmol) were dissolved in 60 mL of DMF in sequence, and the mixture was refluxed and stirred overnight. After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into 100 mL of ice water to precipitate a precipitate, which was filtered and rinsed with 20 mL of water. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1 : 2) Purification to obtain white solid compound 23-4 (4.0 g, yield: 54%).

MS(ESI, pos.ion) m/z: 290.0 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.62 (s, 1H), 7.69 (dd, J=14.2, 4.4 Hz, 2H), 7.57-7.51 (m, 1H), 7.37 (d, J=7.9 Hz) , 1H), 7.18 (tt, J=14.9, 7.3 Hz, 3H) ppm.

Step 4: Synthesis of Compound 23-5

In a 100mL round-bottomed flask, compound 23-4 (500mg, 1.73mmol), POCl ₃ (180ul, 1.90mmol), and N,N-dimethylaniline (85uL, 0.692mmol) were added to 30mL of toluene in turn, and the reaction solution Stir at reflux overnight. After the reaction was completed, cool to room temperature, add 10 mL of water to quench the reaction, extract with dichloromethane (10 mL×3), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and remove under reduced pressure Organic solvent, the obtained crude product 23-5 was directly subjected to the next step without further purification.

Step 5: Synthesis of Compound 23-6

NaH (60% dispersed in mineral oil, 53 mg, 1.3 mmol) was added to a 100 mL round bottom flask, 20 mL of anhydrous DMF was added under nitrogen protection, cooled in an ice bath, and compound 2-7 (250 mg, 0.65 mmol) was added. The reaction mixture was warmed to room temperature and stirred. When no bubbles were generated in the reaction, 20 mL of a THF solution containing compound 23-5 (150 mg, 0.65 mmol) was added and stirred at room temperature overnight. After the reaction, 1 mL of water was added to quench the reaction, the pH was adjusted to <7 with dilute hydrochloric acid solution, extracted with ethyl acetate (30 mL×3), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, After filtration, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:2) to obtain a white solid compound 23-6 (50 mg, yield: 16 %).

MS (ESI, pos.ion) m/z: 503.1 [M+H] ⁺ .

Step 6: Synthesis of Compound 23-7

Compound 23-6 (775 mg, 1.54 mmol), compound 1-9 (620 mg, 1.54 mmol), EDCI (310 mg, 1.62 mmol), HOAT (240 mg, 1.69 mmol) were added to a 100 mL round-bottomed flask, and added under nitrogen protection 10 mL of dichloromethane was cooled in an ice bath, compound DIPEA (660 uL, 3.85 mmol) was added at 0° C., and the reaction solution was warmed to room temperature and stirred overnight. After the reaction, 5 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, and then extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:2) to obtain compound 23-7 as a white solid (560 mg, yield: 51%).

MS(ESI, pos.ion) m/z: 715.0 [M+H] ⁺ ;

Step 7: Synthesis of Compound 23-8

Compound 23-7 (700 mg, 0.98 mmol) was added to a 100 mL round bottom flask, then 20 mL of 5N HCl ethyl acetate solution was slowly added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, a white solid was precipitated, which was filtered, the obtained solid was washed with 20 mL of ethyl acetate, and dried to obtain a white solid compound 23-8 (630 mg, yield: 90%).

Step 8: Synthesis of Compound 23-9

Compound 23-8 (500 mg, 0.75 mmol), compound 2-11 (406 mg, 0.90 mmol), EDCI (190 mg, 1.0 mmol) and HOAT (115 mg, 0.85 mmol) were added to a 100 mL round bottom flask, and added under nitrogen protection 8 mL of dichloromethane, compound DIPEA (350 uL, 2.0 mmol) was added at 0°C, and then the reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, 5 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:2) to obtain white solid compound 23-9 (300 mg, yield: 46%).

MS (ESI, neg.ion) m/z: 866.1 [MH] ^- .

Step 9: Synthesis of Compounds 23-10

Compound 23-9 (300 mg, 0.35 mmol) and Grubbs second-generation catalyst (30 mg, 0.08 mmol) were added to 100 mL of 1,2-dichloroethane, and stirred at 65° C. for 48 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the organic solvent was spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:2) to obtain a white solid compound 23-10 (130 mg, yield: 45%).

MS(ESI, pos.ion) m/z: 840.2[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.32 (s, 1H), 7.48-7.35 (m, 3H), 7.27-7.21 (m, 2H), 7.17 (m, 4H), 7.06 (s, 1H) ,5.92(s,1H),5.73(m,1H),5.21(d,J＝7.3Hz,1H),5.06–4.94(m,1H),4.62(t,J＝7.7Hz,1H),4.55( d, J＝11.4Hz, 1H), 4.34(t, J＝7.6Hz, 2H), 4.02(d, J＝8.0Hz, 1H), 2.92(s, 1H), 2.62(m 3H), 2.33(m ,1H),1.91–1.76(m,6H),1.76–1.28(m,15H),1.21–1.03(m,2H),1.03–0.78(m,2H)ppm;

HPLC purity: 98.25%.

Example 24

synthetic route

Step 1: Synthesis of Compound 24-1

In a 100 mL round-bottomed flask, compound 23-4 (3.0 g, 10.3 mmol), p-fluorophenylboronic acid (1.5 g, 10.3 mmol), Pd(PPh ₃ ) ₄ (300 mg, 0.26 mmol) and K ₂ CO ₃ were sequentially added (7.2 g, 52 mmol), then 90 mL of THF and 30 mL of _H2O were added, and the reaction mixture was stirred at reflux overnight under nitrogen. After the reaction was completed, it was cooled to room temperature, 30 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:2) to obtain white solid compound 24-1 (2.2 g, yield: 69%).

MS (ESI, pos.ion) m/z: 306.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 24-2

Compound 24-1 (2.0 g, 6.6 mmol) was dissolved in 60 mL of toluene, and then POCl ₃ (0.62 mL, 7.3 mmol) and N,N-dimethylaniline (0.34 mL, 2.7 mmol) were added under nitrogen protection, The reaction solution was heated to reflux and reacted overnight. After the reaction was completed, it was cooled to room temperature, 20 mL of water was added to quench the reaction, rinsed once with 20 mL of water, the organic phase was rinsed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product 24-2 did not require Further purification went directly to the next reaction.

Step 3: Synthesis of Compound 24-3

NaH (0.52 g, 13 mmol, 60% dispersed in mineral oil) was added to a 100 mL round-bottomed flask, 30 mL of anhydrous THF was added under nitrogen protection, cooled in an ice bath, and then compound 2-7 (1.5 g, 6.5 mmol) was added . The reaction mixture was warmed to room temperature and stirred until no bubbles were formed, then a solution of compound 24-2 (2.1 g, 6.5 mmol) in 20 mL of THF was added, and the mixture was stirred at room temperature overnight. After the reaction, add water to quench the reaction, adjust the pH value to be less than 7 with dilute hydrochloric acid solution, extract with dichloromethane (50 mL×3), combine the organic phases, wash the organic phases with saturated sodium chloride, and dry over anhydrous magnesium sulfate. Filtration, spin-dried the organic solvent, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 24-3 (2.6 g, yield: 77%) .

MS (ESI, pos.ion) m/z: 519.2 [M+H] ⁺ .

Step 4: Synthesis of Compound 24-4

Compound 24-3 (2.0 g, 3.86 mmol), compound 1-9 (1.56 g, 3.86 mmol), EDCI (780 mg, 4.02 mmol) and HOAT (580 mg, 4.24 mmol) were added to a 100 mL round-bottomed flask under nitrogen protection 25 mL of dichloromethane was added at 0° C., cooled in an ice bath, compound DIPEA (1.86 mL, 10.6 mmol) was added at 0° C., and the reaction mixture was warmed to room temperature and stirred overnight. After the reaction was completed, 10 mL of 1N aqueous hydrochloric acid was added to quench the reaction, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 24-4 (1.7 g, yield: 60%).

MS(ESI, pos.ion) m/z: 731.2 [M+H] ⁺ .

Step 5: Synthesis of Compound 24-5

Compound 24-4 (200 mg, 0.28 mmol) was added to a 100 mL round-bottomed flask, then 20 mL of 5N HCl ethyl acetate solution was slowly added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, a white solid was precipitated, which was filtered, the obtained solid was washed with 20 mL of ethyl acetate, and dried to obtain a white solid compound 24-5 (160 mg, yield: 87%).

Step 6: Synthesis of Compound 24-6

Compound 24-5 (150 mg, 0.23 mmol), compound 2-11 (122 mg, 0.27 mmol), EDCI (56 mg, 0.29 mmol) and HOAT (35 mg, 0.25 mmol) were added to a 10 mL round bottom flask, and added under nitrogen protection 5 mL of dichloromethane was added with compound DIPEA (75 ul, 0.59 mmol) at 0°C. The reaction solution was then warmed to room temperature and stirred overnight. After the reaction was completed, 5 mL of 1N aqueous hydrochloric acid was added to quench the reaction, extracted with dichloromethane (5 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to obtain the crude product It was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 24-6 (80 mg, yield: 40%) as a white solid.

MS (ESI, pos.ion) m/z: 884.3 [M+H] ⁺ .

Step 7: Synthesis of Compound 24-7

Compound 24-6 (400 mg, 0.45 mmol) and Grubbs second-generation catalyst (40 mg, 0.08 mmol) were added to 100 mL of 1,2-dichloroethane, under nitrogen protection, and stirred at 65° C. for 48 hours. After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a white solid compound 24-7 ( 110 mg, yield: 29%). MS(ESI, pos.ion) m/z: 856.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.32 (s, 1H), 7.61 (d, J=6.9 Hz, 1H), 7.53 (m, 2H), 7.36 (s, 1H), 7.30 (d, J =8.8Hz,1H),7.25(d,J=5.7Hz,1H),7.21–7.09(m,4H),7.07(s,1H),5.96(s,1H),5.73(d,J=7.9Hz ,1H),5.23(s,1H),5.07–4.91(m,1H),4.67–4.49(m,1H),4.38(s,1H),4.08(dd,J=15.9,9.1Hz,1H), 2.93(s, 1H), 2.62(d, J=54.7Hz, 3H), 2.34(s, 1H), 2.06(s, 1H), 1.99–1.69(m, 5H), 1.61(s, 2H), 1.41 –1.23(m,12H),1.20-1.05(m,2H),0.95(d,J=7.1Hz,2H)ppm;

HPLC purity: 98.06%.

Example 25

synthetic route

Step 1: Synthesis of Compound 25-1

Compound 25-0 (2.0 g, 12.7 mmol), isopropanol (0.786 g, 13.1 mmol), diphenyl-2-pyridinephosphine (DPPPy, 5.0 g, 19.0 mmol) and di-tert-butyl azodicarboxylate were combined (DBAD, 4.4 g, 19.0 mmol) was dissolved in 100 mL of THF, and the reaction solution was stirred at room temperature for 24 h under nitrogen protection. After the reaction, the organic solvent was removed under reduced pressure, the residue was dissolved in 30 mL of ethyl acetate, washed with 20 mL of 1N HCl solution, dried over anhydrous Na ₂ SO ₄ , and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow oily product 25-1 (2.46 g, yield: 97%).

MS(ESI, pos.ion) m/z: 200.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 25-3

Compound 25-1 (4.0 g, 12 mmol) and compound 25-2 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, and K ₂ CO ₃ (3.41 g, 24.7 mmol) was added thereto. After the addition, the reaction The mixture was warmed to reflux and reacted overnight. After the reaction, it was cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (100 mL×2), washed with 50 mL of saturated brine once, dried over anhydrous Na ₂ SO ₄ , and the organic solvent was removed under reduced pressure to obtain The yellow solid compound 25-3 (4.0 g, yield: 95%) was directly subjected to the next reaction without further purification.

MS (ESI, pos.ion) m/z: 350.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 25-4

Compound 25-3 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was heated to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was filtered off, 1N HCl solution was added dropwise to the filtrate, a large amount of white solid was precipitated, and the obtained white solid was filtered, and the obtained white solid was dried under vacuum to obtain the target compound 25-4 (3.0 g, yield: 91%); proceed to the next step without further purification.

MS (ESI, pos.ion) m/z: 288.2 [M+H] ⁺ .

Step 4: Synthesis of Compound 25-5

Compound 25-4 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain light yellow Solid product 25-5 (1.1 g, 100%).

MS (ESI, pos.ion) m/z: 306.2 [M+H] ⁺ .

Step 5: Synthesis of Compound 25-6

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added After the addition of anhydrous DMF solution, the reaction was warmed to 30°C and stirred for two hours. A solution of compound 25-5 (1.1 g, 3.6 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then reacted overnight. At 0°C, the reaction was quenched with 20 mL of water, rinsed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH around 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, and then saturated with Washed with brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 25- 6 (1.0 g, yield: 56%).

MS (ESI, pos.ion) m/z: 501.3 [M+H] ⁺ .

Step 6: Synthesis of Compound 25-7

Compound 25-6 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen To protect, add 30 mL of dichloromethane, then cool to 0 °C and add DIPEA (1.05 mL, 6.02 mmol). The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure , the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain purified white solid compound 25-7 (0.86 g, yield 60%).

MS (ESI, pos.ion) m/z: 713.4 [M+H] ⁺ .

Step 7: Synthesis of Compound 25-9

Compound 25-7 (0.86 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 20 mL of a 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature until The reaction ends when no gas is evolved. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 mL of dichloromethane was added, and then Cool to 0 °C and add DIPEA (0.6 mL, 3.0 mmol). The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 25-9 (0.92 g, yield 98%).

MS(ESI, pos.ion) m/z: 866.2 [M+H] ⁺ .

Step 8: Synthesis of Compounds 25-10

Compound 25-9 (0.5 g, 0.58 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 65 °C and stirred for 48 hours . After the reaction, it was cooled to room temperature, and the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 25-10 (0.25 g, Yield: 48%).

HPLC purity: 96.62%;

MS(ESI, pos.ion) m/z: 838.4[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ10.35(s,1H), 7.63-7.40(m,1H), 7.15-7.04(m,1H), 6.90-6.81(m,2H), 6.77-6.62( m, 2H), 5.87(s, 1H), 5.72(d, J=8.9Hz, 1H), 5.29(s, 1H), 4.99(t, J=9.4Hz, 1H), 4.71–4.58(m, 1H ), 4.56–4.46 (m, 2H), 4.40–4.26 (m, 1H), 4.11–3.96 (m, 1H), 2.92 (s, 1H), 2.70–2.49 (m, 3H), 2.33 (d, J = 8.3Hz, 1H), 1.97-1.83 (m,, 4H), 1.48-1.30 (m, 23H), 1.17-1.08 (m, 2H), 0.94-0.88 (m, 2H) ppm.

Example 26:

synthetic route:

Step 1: Synthesis of Compound 26-1

Compound 26-0 (1.0 g, 5.6 mmol) was slowly added dropwise with concentrated sulfuric acid (1.5 mL, 27 mmol) under an ice bath, followed by nitric acid (0.5 mL, 7 mmol), and then reacted under an ice bath for 4 hours. After the reaction was completed, the reaction solution was slowly raised to room temperature, then poured into 20 mL of ice water, extracted with ethyl acetate (15 mL x 3), and the extract was washed with 20 mL of 1N sodium hydroxide solution and saturated sodium chloride solution in turn, and then washed with anhydrous dried over magnesium sulfate. The organic solvent was removed under reduced pressure to obtain the product 26-1 as a pale yellow oil (1.1 g, yield: 88%).

Step 2: Synthesis of Compound 26-3

Compound 26-1 (1.0 g, 4.4 mmol) and compound 26-2 (0.83 g, 4.9 mmol) were dissolved in 20 mL of DMF, and K ₂ CO ₃ (1.2 g, 8.7 mmol) was added thereto, after which the reaction mixture was warmed up to reflux and react overnight. Cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (100 mL×2), and washed with 50 mL of saturated brine once, the organic phase was dried over anhydrous Na ₂ SO ₄ , and the organic solvent was removed under reduced pressure to obtain a yellow solid 26-3 (1.6 g, yield: 96%), which was directly carried out to the next step without further purification.

MS (ESI, pos.ion) m/z: 376.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 26-4

Compound 26-3 (1.0 g, 2.7 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (0.2 g, 4 mmol) was added, and the reaction mixture was heated to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was filtered off, 100 mL of 1N HCl solution was added dropwise to the filtrate, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain the target compound 26-4 (0.6 g, yield : 70%); the next reaction was carried out directly without further purification.

MS (ESI, pos.ion) m/z: 314.0 [M+H] ⁺ .

Step 4: Synthesis of Compound 26-5

Compound 26-4 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain light yellow Solid product 26-5 (0.5 g, 45%).

MS (ESI, pos.ion) m/z: 332.1 [M+H] ⁺ .

Step 5: Synthesis of Compound 26-7

Sodium hydride (60% dispersed in mineral oil, 0.13 g, 3.25 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 of compound 2-7 (0.4 g, 1.73 mmol) was added. mL of anhydrous DMF solution, after which the reaction was warmed to 30°C and stirred for two hours. A solution of compound 26-5 (0.5 g, 1.51 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then the reaction was continued overnight. After the reaction was completed, the reaction was quenched with 20 mL of water at 0 °C, and then rinsed with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20 mL×3), combined The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) , a white solid compound 26-7 was obtained (0.54 g, yield: 68%)

MS (ESI, pos.ion) m/z: 527.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 26-8

Compound 26-7 (0.54 g, 1.0 mmol), compound 1-9 (0.45 g, 1.1 mmol), EDCI (0.26 g, 1.5 mmol) and HOAT (0.16 g, 1.2 mmol) were added to a round-bottomed flask under nitrogen Protection, 30 mL of dichloromethane was added, then cooled to 0 °C, then DIPEA (0.5 mL, 3.0 mmol) was added, the reaction mixture was warmed to 30 °C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain purified white solid compound 26-8 (0.66 g, yield 87%).

MS (ESI, pos.ion) m/z: 739.3 [M+H] ⁺ .

Step 7: Synthesis of Compounds 26-10

Compound 26-8 (0.65 g, 0.88 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 20 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature until The reaction ends when no gas is evolved. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.45 g, 1 mmol), EDCI (0.2 g, 1 mmol) and HOAT (0.13, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 mL of dichloromethane was added, and then cooled to At 0 °C, additional DIPEA (0.45 mL, 2.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted twice with 10 mL of ethyl acetate, the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain purified white solid compound 26-10 (0.66 g, yield 51%). MS (ESI, neg.ion) m/z: 890.4 [MH] ^- .

Step 8: Synthesis of Compounds 26-11

Compound 26-10 (0.34 g, 0.38 mmol) was dissolved in 200 mL of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, and the reaction mixture was heated to 65° C. and stirred for 48 hours. After the reaction, it was cooled to room temperature, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a purified white solid compound 26 -11 (0.2 g, yield: 61%).

MS(ESI, pos.ion) m/z: 863.9[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.42 (s, 1H), 7.65-7.49 (m, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.09-7.04 (m, 2H), 6.96 –6.85(m, 2H), 5.88(s, 1H), 5.73(dd, J=17.8, 8.8Hz, 1H), 5.18(d, J=7.6Hz, 1H), 5.06–4.95(m, 1H), 4.73–4.53 (m, 2H), 4.33 (t, J=7.7Hz, 1H), 4.15–3.94 (m, 1H), 2.97–2.86 (m, 1H), 2.71–2.51 (m, 3H), 2.38– 2.27 (m, 1H), 1.91–1.73 (m, 4H), 1.48–1.29 (m, 17H), 1.15–1.06 (m, 2H), 0.97–0.87 (m, 2H) ppm;

HPLC purity: 95.08%.

Example 27:

synthetic route:

Step 1: Synthesis of Compound 27-1

Compound 27-0 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. The reaction was detected by TLC. After the reaction was completed, the mixture was cooled to 0° C. and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether) to obtain a pale yellow solid product 27-1 (0.7 g, 70%).

MS(ESI, pos.ion) m/z: 266[M+H] ⁺ .

Step 2: Synthesis of Compound 27-2

Sodium hydride (60% dispersed in mineral oil, 0.15 g, 3.8 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 of compound 2-7 (0.42 g, 1.8 mmol) was added. mL of anhydrous DMF solution, then warmed to 30°C and stirred for two hours.

A solution of compound 27-1 (0.43 g, 1.6 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then reacted overnight. At 0°C, the reaction was quenched with 20 mL of water, washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid Compound 27-2 (0.4 g, yield: 54%)

MS (ESI, pos.ion) m/z: 673.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 27-3

Compound 27-2 (0.7 g, 2 mmol), compound 1-9 (0.68 g, 1.7 mmol), EDCI (0.4 g, 2 mmol) and HOAT (0.3 g, 2 mmol) were added to a round-bottomed flask, under nitrogen protection, added 30 mL of dichloromethane was then cooled to 0°C, then DIPEA (0.8 mL, 5 mmol) was added and the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 27-3 (0.95 g, yield 50%).

MS (ESI, pos.ion) m/z: 673 [M+H] ⁺ .

Step 4: Synthesis of Compound 27-5

Compound 27-3 (0.78 g, 1.28 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 20 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature until The reaction ends when no gas is evolved. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.7 g, 1.55 mmol), EDCI (0.32 g, 1.7 mmol) and HOAT (0.21, 1.5 mmol) were added to a round bottom flask, under nitrogen protection, 20 mL of dichloromethane was added, It was then cooled to 0°C and DIPEA (0.7 mL, 4 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 27-5 (0.55 g, yield 52%) as a white solid.

MS (ESI, neg.ion) m/z: 824 [MH] ^- .

Step 5: Synthesis of Target 27-6

Compound 27-5 (0.5 g, 0.6 mmol) was dissolved in 400 ml of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, and the reaction mixture was heated to 65° C. and stirred for 48 hours. After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 27-6 (0.37 g, Yield: 80%). MS(ESI, pos.ion) m/z: 798.2[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.34(s, 1H), 7.64-7.50(m, 1H), 7.21-7.02(m, 2H), 6.95-6.82(m, 3H), 5.89(s, 1H), 5.73(dd, J＝17.4, 8.6Hz, 1H), 5.20(d, J＝7.2Hz, 1H), 5.00(t, J＝9.3Hz, 1H), 4.76–4.46(m, 2H), 4.32(d,J＝7.6Hz,1H),4.13-3.97(m,1H),2.92(s,1H),2.62(t,J＝18.0Hz,3H),2.37-2.27(m,1H),1.95 –1.77(m,4H),1.48–1.28(m,17H),1.16–1.09(m,2H),0.91–0.88(m,2H)ppm;

HPLC purity: 97.74%.

Example 28:

synthetic route:

Step 1: Synthesis of Compound 28-1

Compound 28-0 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and N,N-dimethylaniline (0.2 mL, 7.0 mmol) was added slowly. 1.4 mmol), the reaction mixture was warmed to 110° C. and reacted for 6 hours. The reaction was detected by TLC. After the reaction was complete, the mixture was cooled to 0° C. and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether) to obtain a pale yellow solid product 28-1 (0.7 g, 70%).

MS(ESI, pos.ion) m/z: 266[M+H] ⁺ .

Step 2: Synthesis of Compound 28-2

Sodium hydride (60% dispersed in mineral oil, 0.15 g, 3.8 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 of compound 2-7 (0.42 g, 1.8 mmol) was added. mL of anhydrous DMF solution, after which the reaction was warmed to 30°C and stirred for two hours. A solution of compound 28-1 (0.43 g, 1.6 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then reacted overnight. After the reaction was completed, the reaction was quenched with 20 mL of water at 0°C, rinsed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the organic The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1), A white solid compound 28-2 was obtained (0.4 g, yield: 54%) MS (ESI, neg.ion) m/z: 459 [MH] ⁻ .

Step 3: Synthesis of Compound 28-3

Compound 28-2 (0.7 g, 2 mmol), compound 1-9 (0.68 g, 1.7 mmol), EDCI (0.4 g, 2 mmol) and HOAT (0.3 g, 2 mmol) were added to a round-bottomed flask, under nitrogen protection, added 30 mL of dichloromethane was then cooled to 0° C., DIPEA (0.8 mL, 5 mmol) was added, and the reaction solution was heated to 30° C. and stirred for 4 hours. The reaction was quenched with 10 mL of water, extracted with 20 mL of ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The product was purified with silica gel column (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 28-3 as a white solid (0.95 g, yield 50%).

MS (ESI, pos.ion) m/z: 673 [M+H] ⁺ .

Step 4: Synthesis of Compound 28-5

Compound 28-3 (0.78 g, 1.28 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 20 mL of a 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature until The reaction ends when no gas is evolved. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.7 g, 1.55 mmol), EDCI (0.32 g, 1.7 mmol) and HOAT (0.21, 1.5 mmol) were added to a round bottom flask, under nitrogen protection, 20 mL of dichloromethane was added, It was then cooled to 0°C and further DIPEA (0.7 mL, 4 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 28-5 (0.55 g, yield 52%).

MS (ESI, neg.ion) m/z: 824 [MH] ^- .

Step 5: Synthesis of Target 28-6

Compound 28-5 (0.5 g, 0.6 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, and the reaction mixture was heated to 65° C. and stirred for 48 hours. After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 28-6 ( 0.26 g, yield: 54%).

MS(ESI, pos.ion) m/z: 798[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.49 (s, 1H), 7.78-7.42 (m, 2H), 7.14-6.99 (m, 1H), 6.97-6.88 (m, 3H), 5.96-5.84 ( m, 1H), 5.75–5.62 (m, 1H), 5.45 (d, J=5.7Hz, 1H), 5.05–4.89 (m, 1H), 4.81–4.48 (m, 2H), 4.33 (s, 1H) ,4.21–4.01(m,1H),2.90(s,1H),2.70–2.52(m,3H),2.39–2.19(m,2H),1.95–1.77(m,3H),1.52–1.28(m, 17H), 1.14–1.05 (m, 2H), 0.91–0.86 (m, 2H) ppm;

HPLC purity: 98.85%.

Example 29:

synthetic route:

Step 1: Synthesis of Compound 29-2

Compound 29-1 (3.0 g, 12.2 mmol) was added to toluene (100 mL), POCl ₃ (3.7 g, 24.4 mmol) and N,N-dimethylaniline (157 mg, 1.22 mmol) were slowly added with stirring. After completion, the reaction solution was heated and refluxed for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 29-2 as a pale yellow solid (1.1 g, yield: 33%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.77 (dd, J=7.8, 1.2 Hz, 1H), 7.52-7.43 (m, 3H), 7.41 (td, J=7.6, 1.5 Hz, 1H), 7.34 (dd, J=7.3, 1.3 Hz, 1H), 7.31 (dd, J=7.9, 1.4 Hz, 1H), 7.20 (td, J=7.7, 1.5 Hz, 1H) ppm.

Step 2: Synthesis of Compound 29-3

The compound N-Boc-4-(R)-hydroxyproline methyl ester (2-7, 1.5 g, 6.1 mmol) was dissolved in THF (100 mL), and NaH (60% dispersed in in mineral oil, 500 mg, 6.1 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. Compound 29-2 (1.5 g, 6.1 mmol) was then dissolved in a small amount of THF, added to the above solution, and stirring was continued for 12 hours. After the reaction, the reaction solution was poured into 50 mL of water, adjusted to pH 2-3 with 1N HCl, extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, The organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 29-3 (1.1 g, yield: 36.6%) ).

MS(ESI, pos.ion) m/z: 441.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.58-7.39 (m, 4H), 7.35 (t, J=7.2 Hz, 1H), 7.28 (m, 1H), 7.17 (d, J=7.6 Hz, 1H) ), 7.08(s, 1H), 5.77(d, J=13.9Hz, 1H), 4.57(m, 1H), 4.16–3.82(m, 2H), 2.64(m, 2H), 1.49(s, 9H) ppm. .

Step 3: Synthesis of Compound 29-4

Compound 29-3 (200 mg, 0.45 mmol), 1-9 (182 mg, 0.45 mmol), EDCI (112 mg, 0.59 mmol) and HOAT (67.5 mg, 0.49 mmol) were added to 5 mL of CH ₂ Cl ₂ under nitrogen protection and Under ice bath, DIPEA (0.2 mL, 1.18 mmol) was added. After the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 29-4 (150 mg, yield: 57.6%) as a white solid.

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.07 (s, 1H), 7.47 (dt, J=19.1, 7.6 Hz, 4H), 7.37 (d, J=7.0 Hz, 1H), 7.23-7.06 (m ,3H),5.80(br,2H),5.33(d,J＝17.2Hz,1H),5.19(d,J＝10.4Hz,1H),4.42–4.33(m,1H),3.99–3.80(m, 2H), 3.02–2.92(m, 1H), 2.57(s, 1H), 2.22–2.07(m, 1H), 2.01(s, 1H), 1.50(s, 10H), 1.36(s, 2H), 1.06 (d, J=5.4 Hz, 2H) ppm.

Step 4: Synthesis of Compound 29-5

Compound 29-4 (150 mg, 0.27 mmol) was dissolved in 20 mL of 5N HCl in EA solution, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 10 mL of CH ₂ Cl ₂ , and compound 2-11 (41 mg, 0.27 mmol), EDCI (67.4 mg, 1.35 mmol) and HOAT (40 mg, 0.29 mmol) were added simultaneously, under nitrogen protection, added under ice bath DIPEA (1.2 mL, 0.70 mmol), after which the reaction was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 29-5 (150 mg, yield: 68.5%) as a white solid.

Step 5: Synthesis of Compound 29-6

Compound 29-5 (150 mg, 0.18 mmol) was dissolved in 1,2-dichloroethane (100 mL), Grubbs second-generation catalyst (15 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 29-6 as a white solid (60 mg, yield: 40%).

MS(ESI, pos.ion) m/z: 779.1[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.26 (br, 1H), 7.47 (t, J=6.9 Hz, 3H), 7.39 (m, 1H), 7.29 (m, 3H), 7.22 (s, 1H) ),7.08(s,1H),6.81(br,1H),5.96(s,1H),5.84–5.71(m,1H),5.21–5.12(m,1H),5.10–5.00(m,1H), 4.67–4.58 (m, 2H), 4.47–4.36 (m, 1H), 4.11–4.04 (m, 1H), 3.00–2.89 (m, 1H), 2.67 (m, 1H), 2.40–2.27 (m, 1H) ), 2.02–1.77 (m, 3H), 1.25–150 (m, 18H), 1.22–1.08 (m, 2H), 1.06–0.83 (m, 2H) ppm;

HPLC purity: 97.84%.

Example 30:

synthetic route:

Step 1: Synthesis of Compound 30-3

Compound 30-1 (5.0 g, 31.4 mmol) and compound 30-2 (5.3 g, 34.5 mmol) were dissolved in DMF (200 mL), K ₂ CO ₃ (8.7 g, 62.8 mmol) was added, and the reaction mixture was heated at 65° C. under stirring for about 4 hours. After completion of the reaction, the reaction solution was poured into 500 mL of water, a yellow solid was precipitated, filtered, and the filter cake was washed successively with 50 mL of 1N NaOH aqueous solution and 50 mL of water, and the obtained solid was dried in vacuum to obtain a pale yellow solid compound 30-3 (3.6 g, Yield: 74%).

MS (ESI, neg.ion) m/z: 292.0 [MH] ^- .

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.22–8.26 (m 1H), 8.09–8.11 (m, 1H), 7.60–7.61 (m, 3H), 6.91–6.95 (m, 1H), 5.52–6.55 (m,1H)ppm.

Step 2: Synthesis of Compound 30-4

Compound 30-3 (3 g, 10.5 mmol), iron powder (1.72 g, 17.8 mmol) and glacial acetic acid (120 mL) were sequentially added to a round-bottomed flask, and the reaction mixture was stirred at 110° C. for about 12 hours. After the reaction was completed, the solvent was evaporated to about 30 mL, then 100 mL of water was added, and a solid was precipitated, filtered, and the filter cake was washed three times with 20 mL of water, and the obtained solid was vacuum-dried and used directly for the next reaction without further purification. MS(ESI, pos.ion) m/z: 246.0 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.66 (br, 1H), 7.68-7.70 (m, 1H), 7.44-7.52 (m, 4H), 7.24-7.26 (m, 2H).

Step 3: Synthesis of Compound 30-5

Compound 30-4 (3.0 g, 12.2 mmol) was added to 100 mL of toluene, and POCl ( _3.7 g, 24.4 mmol) and N,N-dimethylaniline (157 mg, 1.22 mmol) were slowly added under stirring. , the reaction solution was heated and refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 30-5 as a pale yellow solid (1.1 g, yield: 33%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.81-7.83 (m, 1H), 7.62-7.64 (m, 1H), 7.56-7.58 (m, 2H), 7.43-7.45 (m, 1H), 7.31- 7.34 (m, 2H) ppm.

Step 4: Synthesis of Compound 30-6

Compound 2-7 (1.11 g, 4.56 mmol) was dissolved in 20 mL of THF, NaH (60%, 365 mg, 9.12 mmol) was added in batches under ice bath, and the mixture was heated to room temperature and stirred for 30 minutes. Compound five 30-5 was dissolved in 5 mL of THF, added to the above reaction solution, and continued to stir for 12 hours. After the reaction, the reaction solution was poured into 300 mL of water, adjusted to pH 2-3 with 1N HCl, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 30-6 (1.1 g, yield: 47.6%).

MS(ESI, pos.ion) m/z: 459.1 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.38-7.39 (m, 2H), 7.33-7.35 (m, 1H), 7.26-7.29 (m, 1H), 7.09-7.10 (m, 1H), 6.99- 7.02 (m, 1H), 6.88–6.90 (m, 1H), 5.55 (br s, 1H), 4.31–-4.34 (m, 1H), 3.73–3.86 (m, 2H), 1.99–2.01 (m, 2H) ), 1.5(s,9H)ppm.

Step 5) Synthesis of compound 30-7

Compound 30-6 (526 mg, 2.0 mmol), compound 1-9 (804 mg, 2.0 mmol), EDCI (496 mg, 2.6 mmol) and HOAT (297 mg, 2.2 mmol) were added to 15 mL of CH ₂ Cl ₂ under nitrogen protection, DIPEA (0.95 mL, 5.2 mmol) was added under an ice bath, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 30-7 as a pale yellow solid (586 mg, yield: 44%).

Step 6: Synthesis of Compound 30-8

Compound 30-7 (607 mg, 0.96 mmol) was dissolved in 20 mL of 5N HCl in EtOAc and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The resulting residue was diluted with 10 mL of CH ₂ Cl ₂ , and compound 2-11 (452 mg, 1.0 mmol), EDCI (206 mg, 1.08 mmol) and HOAT (123 mg, 0.91 mmol) were added simultaneously, under nitrogen protection, DIPEA (0.38 mmol) was added under an ice bath. mL, 2.1 mmol), then warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain Compound 30-8 (406 mg, yield: 47.2%) as a white solid.

Step 7: Synthesis of Compound 30-9

Intermediate 30-8 (406 mg, 0.49 mmol) was dissolved in 1,2-dichloroethane (200 mL), Grubbs second-generation catalyst (50 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give 30-9 as a white solid (140 mg, yield: 35%).

¹ H NMR (600MHz, CDCl ₃ )δ10.24(br,1H), 7.39-7.52(m,3H), 7.31-7.32(m,1H), 7.15-7.21(m,2H), 6.97-7.02(m ,1H),6.86(br,1H),5.14–5.25(m,1H),4.99–5.02(m,1H),4.60–4.63(m,1H),4.35–4.40(m,1H),3.04–4.07 (m, 1H), 2.89–2.99 (m, 1H), 2.53–2.66 (m, 3H), 2.28–2.36 (m, 1H), 1.72–1.96 (m, 6H), 1.27–2.50 (m, 15H) ,0.96–1.18(m,6H)ppm;

HPLC purity: 97.13%.

Example 31:

synthetic route:

Step 1: Synthesis of Compound 31-3

Compound 31-1 (5.0 g, 31.4 mmol) and compound 31-2 (5.3 g, 34.5 mmol) were dissolved in DMF (200 mL), K ₂ CO ₃ (8.7 g, 62.8 mmol) was added, and the reaction mixture was heated at 65° C. under stirring for about 4 hours. After the completion of the reaction, the reactant was poured into 500 mL of water, a yellow solid was precipitated, filtered, and the filter cake was washed successively with 50 mL of 1N NaOH aqueous solution and 50 mL of water, and the obtained solid was dried in vacuo to obtain a pale yellow solid compound 31-3 (3.6 g, produced rate: 74%).

MS (ESI, neg.ion) m/z: 292.1 [MH] ^- .

Step 2: Synthesis of Compound 31-4

Compound 31-3 (1.0 g, 3.4 mmol), iron powder (1.0 g, 17.8 mmol), glacial acetic acid (80 mL) were sequentially added to a round-bottomed flask, and the reaction mixture was stirred at 110° C. for about 12 hours. After the reaction was completed, the solvent was evaporated to about 20 mL, and then 100 mL of water was added, and a solid was precipitated, filtered, and the filter cake was rinsed three times with 20 mL of water, and the obtained product 31-4 was dried in vacuum and used for the next reaction without further purification. .

Step 3: Synthesis of Compound 31-5

Compound 31-4 (1.5 g, 6.1 mmol) was added to 70 mL of toluene, POCl ₃ (2.8 g, 18.0 mmol) and N,N-dimethylaniline (78.9 mg, 0.61 mmol) were slowly added under stirring, and the addition was complete. After that, the reaction solution was heated and refluxed for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 31-5 as a pale yellow solid (770 mg, yield: 47%).

Step 4: Synthesis of Compound 31-6

Compound 2-7 (664 mg, 2.9 mmol) was dissolved in 20 mL of THF, and NaH (60% dispersed in mineral oil, 351 mg, 8.78 mmol) was added in batches under ice bath. After the addition, the reaction mixture was warmed to room temperature and stirred 30 minutes.

The intermediate compound 31-5 was dissolved in 5 mL of THF, added to the above solution, and stirring was continued for 12 hours. After the reaction, the reaction solution was poured into 300 mL of water, adjusted to pH 2-3 with 1N HCl, extracted with ethyl acetate (20 mL×3), combined with the organic phases, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 31-6 (1.12 g, yield: 89.4%) ).

Step 5: Synthesis of Compound 31-7

Compound 31-6 (500 mg, 1.09 mmol), compound 1-9 (438 mg, 1.09 mmol), EDCI (271 mg, 1.41 mmol) and HOAT (147 mg, 1.09 mmol) were added to 15 mL of CH ₂ Cl ₂ under nitrogen protection, DIPEA (422 mg, 3.27 mmol) was added under an ice bath, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 31-7 as a pale yellow solid (580 mg, yield: 43.7%).

Step 6: Synthesis of Compounds 31-8

Compound 31-7 (580 mg, 0.84 mmol) was dissolved in 20 mL of 5N HCl in ethyl acetate, and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue was diluted with 10 mL of CH ₂ Cl ₂ , and at the same time compound 2-11 (876 mg, 1.94 mmol), EDCI (160 mg, 0.86 mmol) and HOAT (87 mg, 0.64 mmol) were added, under nitrogen protection, DIPEA (0.40 mmol) was added under ice bath. mL, 1.93 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 31-8 (300 mg, yield: 43.4%) as a white solid.

Step 7: Synthesis of Compounds 31-9

Intermediate 31-8 (300 mg, 0.36 mmol) was dissolved in 1,2-dichloroethane (200 mL), Grubbs second-generation catalyst (30 mg) was added under nitrogen protection, and the reaction mixture was heated to 65° C. for 48 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 31-9 (140 mg, yield: 48%) as a white solid.

MS(ESI, pos.ion) m/z: 780.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.35 (s, 1H), 7.58-7.35 (m, 4H), 7.29 (s, 1H), 6.94 (d, J=9.0 Hz, 1H), 6.79 (d , J＝6.1Hz, 1H), 5.91(s, 1H), 5.73(dd, J＝17.7, 8.7Hz, 1H), 5.35–5.26(m, 1H), 5.00(t, J＝9.3Hz, 1H) ,4.64(s,1H),4.39(t,J＝7.6Hz,1H),4.06(d,J＝7.8Hz,1H),2.92(s,1H),2.63(d,J＝35.1Hz,3H) , 2.44–2.27 (m, 1H), 1.98–1.79 (m, 3H), 1.44 (m, 20H), 1.12 (m 2H), 0.91 (m, 1H) ppm.

Example 32:

synthetic route:

Step 1: Synthesis of Compound 32-3

The compound 4-bromo-2-fluoronitrobenzene (32-1, 3.30 g, 15 mmol), 4-methoxybenzeneboronic acid (32-2, 2.74 g, 18 mmol), Pd(PPh ₃ ) ₄ (0.5 g, 0.45 mmol) and K2CO3 (10.35 _g , 75 mmol) _were dissolved in THF (80 mL) and water (20 mL) under nitrogen blanket and the reaction mixture was stirred at room temperature overnight. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, reduced The solvent was evaporated under pressure to obtain yellow solid compound 32-3 (3.2 g, yield 87%).

MS (ESI, pos.ion) m/z: 248.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 32-5

Compound 32-3 (1.83 g, 7.4 mmol) and compound 32-4 (1.35 g, 7.4 mmol) were dissolved in DMF (20 mL), K ₂ CO ₃ (1.12 g, 8.1 mmol) was added, and the reaction mixture was warmed to 110° C. React overnight. After the reaction, the reaction solution was quenched by adding water, adjusted to pH 2-3 with 1N HCl, extracted with ethyl acetate (50 mL×3), the extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced in pressure. The organic solvent was removed under the following conditions to obtain the crude product of 32-5 as an orange oily liquid, which was directly carried out to the next step of the reaction.

MS (ESI, pos.ion) m/z: 410 [M+H] ⁺ .

Step 3: Synthesis of Compound 32-6

The crude compound 32-5 was dissolved in glacial acetic acid (100 mL), iron powder (2.1 g, 37 mmol) was added, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and poured into water (200 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a yellow solid compound 32-6 (1.5 g, two-step yield 64 %).

MS (ESI, pos.ion) m/z: 348 [M+H] ⁺ .

Step 4: Synthesis of Compound 32-7

Compound 32-6 (1.5 g, 4.3 mmol) was suspended in toluene (20 mL), POCl ₃ (1.3 g, 8.6 mmol) and N,N-dimethylaniline (0.21 g, 1.8 mmol) were slowly added with stirring, After completion, the reaction solution was heated and refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 32-7 as a pale yellow solid (1.0 g, yield 65%).

MS(ESI, pos.ion) m/z: 366[M+H] ⁺ .

Step 5: Synthesis of Compound 32-8

N-Boc-4-(R)-hydroxyproline (2-7, 1.0 g, 2.8 mmol) was dissolved in DMF (20 mL), and NaH (60% dispersed in mineral oil, 0.34 mL) was added in portions under ice bath g, 8.4 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. Compound 32-7 (0.78 g, 3.3 mmol) was dissolved in a small amount of DMF, added to the above solution, and stirring was continued for 12 hours. After the reaction, the reaction solution was poured into 30 mL of water, and the pH was adjusted to 2-3 with 1N HCl, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phases were washed with saturated sodium chloride solution, and anhydrous It was dried over sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 32-8 (1.3 g, yield 83%).

MS (ESI, pos.ion) m/z: 561 [M+H] ⁺ .

Step 6: Synthesis of Compound 32-9

Compound 32-8 (1.3 g, 2.3 mmol), compound 1-9 (1.13 g, 2.8 mmol), EDCI (570 mg, 3.0 mmol) and HOAT (380 mg, 2.8 mmol) were suspended in CH ₂ Cl ₂ (30 mL) , DIPEA (1.2 mL, 6.9 mmol) was added under an ice bath. After the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, 10 mL of 1N aqueous hydrochloric acid was added to quench the reaction, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification to obtain compound 32-9 as a pale yellow solid (1.6 g, yield 89%).

MS (ESI, pos.ion) m/z: 723 [M+H] ⁺ .

Step 7: Synthesis of Compounds 32-11

Compound 32-9 (1.6 g, 2.07 mmol) was dissolved in 5N HCl in ethyl acetate (20 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure to obtain solid compound 32-10.

The solid compound 32-10 obtained above was added to CH ₂ Cl ₂ (40 mL), followed by compound 2-11 (1.1 g, 2.37 mmol), EDCI (490 mg, 2.56 mmol) and HOAT (320 mg, 2.37), ice bath Then, DIPEA (1.03 mL, 5.91 mmol) was added, and then the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of 1N aqueous hydrochloric acid, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 32-11 (1.4 g, yield 73%) as a light yellow solid after purification.

MS(ESI, pos.ion) m/z: 926[M+H] ⁺ .

Step 8: Synthesis of Compounds 32-12

Compound 32-11 (500 mg, 0.54 mmol) was dissolved in 1,2-dichloroethane (500 mL), Grubbs second-generation catalyst (50 mg) was added under nitrogen protection, and the reaction mixture was heated to 65° C. for 48 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by preparative HPLC to obtain the target compound 32-12 as a white solid (330 mg, yield 68%).

MS(ESI, pos.ion) m/z: 898[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.29 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.48 (d, J=1.4 Hz, 1H), 7.39-7.34 (m, 1H) ), 7.14–7.03 (m, 3H), 7.02–6.92 (m, 3H), 5.99 (s, 1H), 5.74 (dd, J=17.4, 8.6Hz, 1H), 5.17 (d, J=6.1Hz, 1H), 5.02(t, J=9.3Hz, 1H), 4.81–4.47(m, 2H), 4.38(s, 1H), 4.07(d, J=9.0Hz, 1H), 3.93(s, 3H), 3.87(s, 3H), 2.93(s, 1H), 2.74-2.49(m, 3H), 2.34(dd, J=16.6, 8.2Hz, 1H), 2.02-1.80(m, 5H), 1.62(s, 1H), 1.39–1.28 (m, 15H), 1.16–1.08 (m, 2H), 0.94–0.86 (m, 2H) ppm;

HPLC purity: 95.68%.

Example 33:

synthetic route:

Step 1: Synthesis of Compound 33-3

Compound 4-bromo-2-fluoronitrobenzene (33-1, 4.4 g, 20 mmol), 4-methoxybenzeneboronic acid (33-2, 3.73 g, 22 mmol), Pd(PPh ₃ ) ₄ (0.7 g , 0.6 mmol) and K ₂ CO ₃ (13.8 g, 100 mmol) were dissolved in acetonitrile, mixed in THF (80 mL) and water (20 mL) and stirred at room temperature overnight. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), the extract was dried with anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain yellow solid compound 33 -3 (4.8 g, 90% yield).

Step 2: Synthesis of Compound 33-5

Compound 33-3 (1.1 g, 6 mmol) and compound 33-4 (1.6 g, 6 mmol) were dissolved in DMF (20 mL), K ₂ CO ₃ (1.66 g, 12 mmol) was added, and the reaction mixture was heated to 110° C. to react overnight . After the reaction was completed, 20 mL of water was added to quench the reaction, then the pH was adjusted to 2-3 with 1N HCl, extracted with ethyl acetate (50 mL×3), the organic phases were combined, the extract was washed with saturated sodium chloride solution, anhydrous Dry over sodium sulfate, filter, and remove the organic solvent under reduced pressure to obtain the crude product 33-5 as an orange oily liquid, which is directly carried out to the next step.

MS(ESI, pos.ion) m/z: 428[M+H] ⁺ .

Step 3: Synthesis of Compound 33-6

The crude compound 33-5 was dissolved in glacial acetic acid (100 mL), iron powder (1.68 g, 30 mmol) was added, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was poured into water (200 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a yellow solid compound 33-6 (2.1 g, two-step yield 100 %).

MS(ESI, pos.ion) m/z: 366[M+H] ⁺ .

Step 4: Synthesis of Compound 33-7

Compound 33-6 (1.0 g, 2.74 mmol) was suspended in toluene ( ₂₀ mL), POCl (0.84 g, 5.48 mmol) and N,N-dimethylaniline (0.13 g, 1.09 mmol) were slowly added with stirring, After the addition, the temperature was raised and refluxed for 3 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 33-7 as a pale yellow solid (700 mg, yield 67%).

MS(ESI, pos.ion) m/z: 384[M+H] ⁺ .

Step 5: Synthesis of Compound 33-8

The compound N-Boc-4-(R)-hydroxyproline (2-7, 795 mg, 3.4 mmol) was dissolved in DMF (20 mL), and NaH (60% dispersed in mineral oil) was added in portions under an ice bath. 348 mg, 8.7 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. Compound 33-7 (1.1 g, 2.9 mmol) was dissolved in a small amount of DMF, added to the above reaction, and stirring was continued for 2 hours. After the reaction, the reaction solution was poured into 30 mL of water, the pH value was adjusted to 2-3 with 1N HCl aqueous solution, extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride solution , dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 33- 8 (1.5 g, 89% yield).

MS (ESI, pos.ion) m/z: 579 [M+H] ⁺ .

Step 6: Synthesis of Compound 33-9

Compound 33-8 (800 mg, 1.38 mmol), compound 1-9 (668 mg, 1.66 mmol), EDCI (344 mg, 1.8 mmol) and HOAT (224 mg, 1.66 mmol) were suspended in CH ₂ Cl ₂ (25 mL) over ice DIPEA (0.72 mL, 4.14 mmol) was added under the bath. After the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 1N aqueous hydrochloric acid, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced in pressure. The organic solvent was removed under low temperature, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 33-9 (1.0 g, yield 91%) as a light yellow solid. MS (ESI, pos.ion) m/z: 791 [M+H] ⁺ .

Step 7: Synthesis of Compounds 33-11

Compound 33-9 (1.0 g, 1.26 mmol) was dissolved in 5N HCl in ethyl acetate (20 mL) and stirred at room temperature for 3 hours. After the reaction was completed, the organic solvent was removed under reduced pressure. The obtained residue was diluted with CH ₂ Cl ₂ (20 mL), then compound 2-11 (634 mg, 1.4 mmol), EDCI (290 mg, 1.52 mmol) and HOAT (190 mg, 1.4 mol) were added, and DIPEA (0.6 mL) was added under ice bath. , 3.51 mmol), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of 1N aqueous hydrochloric acid, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 33-11 (1.0 g, yield 84%) as a light yellow solid. MS (ESI, pos.ion) m/z: 944 [M+H] ⁺ .

Step 8: Synthesis of Compounds 33-12

Compound 33-11 (500 mg, 0.53 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs second-generation catalyst (50 mg) was added under nitrogen protection, and the reaction mixture was heated to 65° C. for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by preparative HPLC to obtain compound 33-12 as a white solid (300 mg, yield 62%).

MS(ESI, pos.ion) m/z: 916[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ 10.33(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36-7.30(m, 4H), 7.28-7.23(m, 1H), 7.04- 7.00(m, 1H), 6.78-6.62(m, 2H), 5.93(s, 1H), 5.74(dd, J=17.0, 8.4Hz, 1H), 5.24(s, 1H), 5.01(t, J= 9.3Hz, 1H), 4.79–4.43 (m, 2H), 4.42–4.30 (m, 1H), 4.04 (d, J=8.8Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 2.93(s, 1H), 2.74-2.49(m, 3H), 2.35(d, J=8.3Hz, 1H), 1.99-1.72(m, 5H), 1.61(s, 1H), 1.45-1.31(m, 15H), 1.18–1.07 (m, 2H), 0.98–0.89 (m, 2H) ppm;

HPLC purity: 94.25%.

Example 34:

synthetic route:

Step 1: Synthesis of Compound 34-3

Compound 4-bromo-2-fluoronitrobenzene (34-1, 4.4 g, 20 mmol), 4-methoxybenzeneboronic acid (34-2, 3.73 g, 22 mmol), Pd(PPh ₃ ) ₄ (0.7 g , 0.6 mmol) and K ₂ CO ₃ (13.8 g, 100 mmol) were dissolved in acetonitrile in THF (80 mL) and water (20 mL), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, saturated sodium chloride solution (200 mL) was added to quench, extracted with ethyl acetate (3×50 mL), the organic phases were combined, the extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The organic solvent was removed to obtain yellow solid compound 34-3 (4.8 g, yield 90%).

Step 2: Synthesis of Compound 34-5

Compound 34-3 (1.0 g, 6 mmol) and compound 34-4 (1.6 g, 6 mmol) were dissolved in DMF (20 mL), K ₂ CO ₃ (1.66 g, 12 mmol) was added, and the reaction mixture was warmed to 110 ° C and reacted overnight . After the reaction, 30 mL of water was added to quench the reaction, and the pH was adjusted to 2-3 with 1N HCl, then extracted with ethyl acetate (50 mL×3), the extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, Filtration and removal of the organic solvent under reduced pressure gave the crude product 34-5 as an orange oily liquid, which was directly carried out to the next reaction.

MS(ESI, pos.ion) m/z: 416[M+H] ⁺ .

Step 3: Synthesis of Compound 34-6

The crude compound 34-5 was dissolved in glacial acetic acid (100 mL), iron powder (1.68 g, 30 mmol) was added, and the temperature was raised to 110° C. to react for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was poured into water (200 mL), a solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a yellow solid compound 34-6 (1.9 g, two-step yield 89%) ).

MS (ESI, pos.ion) m/z: 354 [M+H] ⁺ .

Step 4: Synthesis of Intermediate 34-7

Compound 34-6 (1.0 g, 2.74 mmol) was suspended in toluene ( ₂₀ mL), POCl (0.84 g, 5.48 mmol) and N,N-dimethylaniline (0.14 g, 1.13 mmol) were slowly added with stirring, After the addition, the reaction mixture was heated and refluxed for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 34-7 (870 mg, yield 85%) as a pale yellow solid.

MS (ESI, pos.ion) m/z: 372 [M+H] ⁺ .

Step 5: Synthesis of Compound 34-8

The compound N-Boc-4-(R)-hydroxyproline (2-7, 688 mg, 2.81 mmol) was dissolved in DMF (20 mL), and NaH (60% dispersed in mineral oil) was added in portions under ice bath. 280 mg, 7.02 mmol), after the addition, the reaction solution was warmed to room temperature and stirred for 30 minutes. Compound 34-7 (870 mg, 2.34 mmol) was dissolved in a small amount of DMF, added to the above reaction solution, and stirring was continued for 2 hours. After the reaction, the reaction solution was poured into 300 mL of water, and the pH value was adjusted to 2-3 with 1N HCl, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the extracted phase was washed with saturated sodium chloride solution. dried over sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 34-8 ( 800 mg, yield 60%).

Step 6: Synthesis of Compound 34-9

Compound 34-8 (800 mg, 1.41 mmol), compound 1-9 (680 mg, 1.69 mmol), EDCI (350 mg, 1.83 mmol) and HOAT (228 mg, 1.69 mmol) were suspended in CH ₂ Cl ₂ (25 mL) over ice DIPEA (0.7 mL, 4.23 mmol) was added under the bath, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 1N aqueous hydrochloric acid, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure , the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 34-9 as a pale yellow solid (650 mg, yield 59%).

MS (ESI, pos.ion) m/z: 779 [M+H] ⁺ .

Step 7: Synthesis of Compounds 34-11

Compound 34-9 (650 mg, 0.83 mmol) was dissolved in 5N HCl in EtOAc (20 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the organic solvent was removed under reduced pressure to obtain compound 34-10 as a white solid. The resulting white solid compound 34-10 was added to _CH2Cl2 ( ₂₀ mL), followed by compound 2-11 (380 mg, 0.84 mmol), EDCI (174 mg, 0.91 mmol) and HOAT (113 mg, 0.84 mol), ice bath DIPEA (0.37 mL, 2.1 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 1N aqueous hydrochloric acid, then extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 34-11 (650 mg, yield 83%) as a pale yellow solid.

MS (ESI, neg.ion) m/z: 930 [MH] ^- .

Step 8: Synthesis of Compounds 34-12

Compound 34-11 (650 mg, 0.70 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs I second-generation catalyst (70 mg) was added under nitrogen protection, and the reaction mixture was heated to 65 °C for 48 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by preparative HPLC to obtain the target compound 34-12 as a white solid (300 mg, yield 48%).

MS(ESI, pos.ion) m/z: 904[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ) δ 10.36 (s, 1H), 7.61-7.51 (m, 1H), 7.37-7.29 (m, 4H), 7.14 (s, 1H), 7.03 (t, J=8.4 Hz, 1H), 6.98–6.83(m, 2H), 5.93(s, 1H), 5.73(dd, J=17.8, 8.7Hz, 1H), 5.26(d, J=7.5Hz, 1H), 5.00(t , J＝9.4Hz,1H),4.74-4.48(m,2H),4.35(dd,J＝13.0,5.3Hz,1H),4.10-3.98(m,1H),3.95(s,3H),2.93( s, 1H), 2.70–2.51 (m, 3H), 2.35 (dd, J=16.7, 8.2Hz, 1H), 2.00–1.78 (m, 4H), 1.73–1.51 (m, 2H), 1.41–1.27 ( m, 14H), 1.16–1.07 (m, 2H), 0.96–0.87 (m, 2H) ppm;

HPLC purity: 96.01%.

Example 35:

synthetic route:

Step 1: Synthesis of Compound 35-2

Compound 35-0 (3 g, 13.63 mmol) and compound 35-1 (2.63 g, 18.65 mmol) were dissolved in 50 mL of DMF, and K ₂ CO ₃ (2.96 g, 21.5 mmol) was added. After the addition, the reaction mixture was warmed to 110 The temperature was refluxed, and the reaction was carried out overnight. It was cooled to room temperature, 100 mL of EtOAc was added, washed with H ₂ O (100 mL×2), washed with 50 mL of saturated brine once, dried over anhydrous Na ₂ SO ₄ , and the organic solvent was removed under reduced pressure. A yellow solid 35-2 was obtained (4 g, yield: 86.95%).

Step 2: Synthesis of Compound 35-3

Compound 35-2 (4.0 g, 11.72 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 100 ml of 1N HCl aqueous solution, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water, and the obtained white solid was dried under vacuum to obtain compound 35-3 ( 3.0 g, yield: 91.74%), directly proceed to the next step without further purification.

Step 3: Synthesis of Compound 35-4

Compound 35-3 (1.0 g, 3.58 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the temperature was raised to 110 °C, and the reaction was carried out for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid Product 35-4 (1.0 g, 94.34%).

Step 4: Synthesis of Compound 35-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added After the addition of anhydrous DMF solution, the reaction mixture was warmed to 30°C and stirred for two hours. A solution of compound 35-4 (1.1 g, 3.7 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then the reaction was continued overnight. After the reaction was completed, the reaction was quenched with 20 mL of water at 0°C, rinsed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, It was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 35 as a white solid. -5 (1.0 g, yield: 56%).

Step 5: Synthesis of Compound 35-6

Compound 35-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen For protection, 30 mL of dichloromethane was added, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, the reaction solution was warmed to 30 °C, and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was used Silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) was purified to obtain compound 35-6 as a white solid (0.86 g, yield 60%).

Step 6: Synthesis of Compound 35-8

Compound 35-6 (0.86 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained by the above filtration, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 ml of dichloromethane were added, It was then cooled to 0°C and DIPEA (0.6 mL, 3.0 mmol) was added. The reaction solution was heated to 30°C and stirred for 4 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) gave Compound 35-8 as a white solid (0.92 g, yield: 98%).

MS (ESI, pos.ion) m/z: 858.5 [M+H] ⁺ .

Step 7: Synthesis of Compound 35-9

Compound 35-8 (0.5 g, 0.58 mmol) was dissolved in 400 ml of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 65 °C and stirred for 48 hours . It was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 35-9 (0.25 g, yield rate: 48%). MS(ESI, pos.ion) m/z: 830.9 [M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.19 (s, 1H), 9.08 (s, 1H), 7.76 (d, J=6.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H ), 7.39–7.30(m, 1H), 7.30–7.25(m, 1H), 7.18(dd, J=26.9, 23.4Hz, 2H), 5.85(d, J=29.2Hz, 1H), 5.60(s, 1H), 5.08(s, 1H), 4.55(dd, J＝30.9, 22.6Hz, 2H), 4.00(d, J＝38.9Hz, 2H), 2.89(s, 1H), 2.05–1.86(m, 1H) ), 1.69(d, J=42.1Hz, 2H), 1.59(s, 2H), 1.49–0.69(m, 22H) ppm;

HPLC purity: 90.49%.

Example 36:

synthetic route:

Step 1: Synthesis of Compound 36-2

Compound 36-0 (4.0 g, 12 mmol) and compound 36-1 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, and then the reaction mixture was heated to reflux, and the reaction overnight. After the reaction was completed, the reaction solution was cooled to room temperature, then 100 mL of EtOAc was added, washed with H ₂ O (100 mL×2), and washed once with 50 mL of saturated brine. The organic phase was dried with anhydrous Na ₂ SO ₄ , and the organic matter was removed under reduced pressure. solvent to obtain a yellow solid 36-2 (4.0 g, yield: 95%), which was directly carried out to the next step without further purification.

Step 2: Synthesis of Compound 36-3

Compound 36-2 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was heated to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was filtered off, the filtrate was poured into 200 ml of 1N HCl solution, a large amount of white solid was precipitated, and the obtained white solid was filtered, and the obtained white solid was dried under vacuum to obtain the target compound 36-3 (3.0 g, yield 36-3). Yield: 91%); the next reaction was carried out directly without further purification.

Step 3: Synthesis of Compound 36-4

Compound 36-3 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. The reaction was detected by TLC. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid Product 36-4 (1.1 g, 100% yield).

Step 4: Synthesis of Compound 36-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added. Aqueous DMF solution, after which the reaction mixture was warmed to 30°C and stirred for two hours. 5 mL of anhydrous tetrahydrofuran solution containing compound 36-4 (1.1 g, 3.6 mmol) was added to the above reaction solution, and then the reaction was continued overnight. At 0°C, the reaction was quenched with 20 mL of water, rinsed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phase was saturated with Washed with brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 36-5 (1.0 g, yield: 56%).

Step 5: Synthesis of Compound 36-6

Compound 36-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen For protection, 30 mL of dichloromethane was added, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, the reaction solution was warmed to 30 °C, and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) gave compound 36-6 as a white solid (0.86 g, yield 60%).

Step 6: Synthesis of Compound 36-8

Compound 36-6 (0.82 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 mL of dichloromethane was added, and then Cool to 0°C and add DIPEA (0.6 mL, 3.0 mmol). The reaction solution was heated to 30°C and stirred for 4 hours. The reaction was quenched with 10 mL of water, extracted twice with 10 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was washed with silica gel Column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) was purified to obtain compound 36-8 as a white solid (0.92 g, yield 98%).

MS (ESI, pos.ion) m/z: 836.5 [M+H] ⁺ .

Step 7: Synthesis of Compound 36-9

Compound 36-8 (0.5 g, 0.58 mmol) was dissolved in 400 ml of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the temperature was raised to 65 °C, and the reaction mixture was at this temperature. Stir for 48 hours. After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 36-9 ( 0.25 g, yield: 48%).

MS(ESI, pos.ion) m/z: 810.4[M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.13 (s, 1H), 7.61 (dd, J=8.4, 6.9 Hz, 1H), 7.26 (dd, J=9.3, 2.1 Hz, 1H), 7.13 (dd, J=18.9, 5.3Hz, 2H), 6.74 (dt, J=8.7, 2.9Hz, 2H), 5.89–5.76 (m, 1H), 5.61 (d, J=7.4Hz, 1H), 5.22– 4.93(m,1H), 4.69–4.39(m,2H), 4.06(s,1H), 3.97–3.84(m,1H), 3.73(s,3H), 2.90(s,1H), 2.72–2.53( m, 2H), 2.45–2.25 (m, 2H), 1.72 (t, J=22.6Hz, 2H), 1.65–1.50 (m, 2H), 1.53–0.67 (m, 22H) ppm;

HPLC purity: 97.43%.

Example 37:

synthetic route:

Step 1: Synthesis of Compound 37-2

Compound 37-0 (4.0 g, 12 mmol) and compound 37-1 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, and the reaction mixture was heated to reflux, React overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of EtOAc was added, washed with H ₂ O (100 mL×2), washed with 50 mL of saturated brine once, the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and removed under reduced pressure organic solvent to obtain a yellow solid 37-2 (4.0 g, yield: 95%), which was directly carried out to the next step without further purification.

Step 2: Synthesis of Compound 37-3

Compound 37-2 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was heated to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100 ml of 1N HCl aqueous solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 37-3 (3.0 g , Yield: 91%).

Step 3: Synthesis of Compound 37-4

Compound 37-3 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 37-4 (1.1 g, 100%).

Step 4: Synthesis of Compound 37-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added Anhydrous DMF solution, after which the reaction mixture was warmed to 30°C and stirred for two hours.

A solution of compound 37-4 (1.1 g, 3.6 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then reacted overnight. After the reaction was completed, the reaction was quenched with 20 mL of water at 0°C, rinsed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined, It was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 37 as a white solid -5 (1.0 g, yield: 56%)

Step 5: Synthesis of Compound 37-6

Compound 37-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen For protection, 30 mL of dichloromethane was added, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, the temperature was raised to 30 °C, and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was used Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) gave compound 37-6 as a white solid (0.86 g, yield 60%).

Step 6: Synthesis of Compound 37-8

Compound 37-6 (0.83 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 20 mL of a 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature until The reaction ends when no gas is evolved. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 mL of dichloromethane was added, and then Cool to 0°C and add DIPEA (0.6 mL, 3.0 mmol). The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 37-8 (0.92 g, yield 98%) as a white solid.

Step 7: Synthesis of Compound 37-9

Compound 37-8 (0.5 g, 0.58 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C, at this temperature Stir for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 37 as a white solid -9 (0.25 g, yield: 48%).

MS(ESI, pos.ion) m/z: 814.3[M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 8.99 (s, 1H), 7.69-7.61 (m, 1H), 7.34 (dd, J=5.8, 3.6 Hz, 1H) ,7.26(d,J＝8.9Hz,1H),7.20(m,1H),7.12(s,1H),5.79(s,1H),5.62(d,J＝7.9Hz,1H),5.07(s, 1H), 4.68(d, J＝11.0Hz, 1H), 4.54–4.47(m, 1H), 4.03(dd, J＝14.2, 7.1Hz, 2H), 3.88(d, J＝10.1Hz, 1H), 2.90(s, 1H), 1.99(s, 1H), 1.91(s, 1H), 1.74(d, J=10.3Hz, 2H), 1.62–1.50(m, 2H), 1.35(s, 5H), 1.27 –0.91(m,18H)ppm;

HPLC purity: 94.18%.

Example 38:

synthetic route:

Step 1: Synthesis of Compound 38-2

Compound 38-0 (4.0 g, 12 mmol) and compound 38-1 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, and the reaction mixture was heated to reflux. overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of EtOAc was added, washed with H ₂ O (100 mL×2), and washed once with 50 mL of saturated brine. The organic phase was dried with anhydrous Na ₂ SO ₄ , and the organic solvent was removed under reduced pressure. , a yellow solid 38-2 (4.0 g, yield: 95%) was obtained, and the next reaction was carried out directly without further purification.

Step 2: Synthesis of Compound 38-3

Compound 38-2 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100 ml of 1N HCl aqueous solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 38-3 (3.0 g, yield : 91%).

Step 3: Synthesis of Compound 38-4

Compound 38-3 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was cooled to 0°C, the organic solvent was removed under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 38-4 (1.1 g, 100%).

Step 4: Synthesis of Compound 38-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added Anhydrous DMF solution, after which the reaction mixture was warmed to 30°C and stirred for two hours. A solution of compound 38-4 (1.1 g, 3.6 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then reacted overnight. At 0°C, the reaction was quenched with 20 mL of water, rinsed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phase was saturated with Washed with brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 38-5 (1.0 g, yield: 56%).

Step 5: Synthesis of Compound 38-6

Compound 38-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen Protected, 30 mL of dichloromethane was added, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, and the reaction mixture was warmed to 30 °C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 38-6 (0.86 g, yield 60%).

Step 6: Synthesis of Compound 38-8

Compound 38-6 (0.83 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid/ethyl acetate solution was added until the reaction ended when no gas was released. Filter and rinse the filter cake with 20 mL of ethyl acetate. The resulting solid, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 mL of dichloromethane was added, and then cooled To 0 °C, DIPEA (0.6 mL, 3.0 mmol) was added. The temperature was raised to 30°C, and the mixture was stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 38-8 (0.92 g, yield 98%).

Step 7: Synthesis of Compound 38-9

Compound 38-8 (0.5 g, 0.58 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C, at this temperature Stir for 48 hours. After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 38-9 ( 0.25 g, yield: 48%).

MS(ESI, pos.ion) m/z: 814.3[M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 8.98 (s, 1H), 7.61 (dd, J=8.6, 6.6 Hz, 1H), 7.41 (d, J=1.8 Hz ,1H),7.37–7.31(m,1H),7.27(dt,J=13.7,5.3Hz,2H),7.13(s,1H),5.78(s,1H),5.69–5.56(m,1H), 5.07(t,J=9.3Hz,1H),4.67(d,J=11.8Hz,1H),4.50(dd,J=9.5,7.2Hz,1H),4.03(s,1H),3.88(d,J ＝10.0Hz, 1H), 3.17(d, J＝5.2Hz, 1H), 2.90(d, J＝5.5Hz, 1H), 2.59(dd, J＝13.8, 6.2Hz, 2H), 2.42–2.27(m ,2H),1.74(d,J＝10.9Hz,2H),1.63-1.52(m,2H),1.37-0.95(m,20H)ppm;

HPLC purity: 96.03%.

Example 39:

synthetic route:

Step 1: Synthesis of Compound 39-2

Compound 39-0 (4.0 g, 12 mmol) and compound 39-1 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, and then the reaction mixture was heated to reflux, and the reaction overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of EtOAc was added, washed with H ₂ O (100 mL×2), and washed once with 50 mL of saturated brine. The organic phase was dried with anhydrous Na ₂ SO ₄ , and the organic solvent was removed under reduced pressure. , a yellow solid 39-2 (4.0 g, yield: 95%) was obtained, and the next reaction was carried out directly without further purification.

Step 2: Synthesis of Compound 39-3

Compound 39-2 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100 ml of 1N HCl aqueous solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 39-3 (3.0 g, yield : 91%).

Step 3: Synthesis of Compound 39-4

Compound 39-3 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was cooled to 0°C, 5 mL of water was added to quench the reaction, and then washed with water (10 mL×2), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure organic solvent to obtain a light yellow solid product 39-4 (1.1 g, 100%), which was directly carried out to the next step without further purification.

Step 4: Synthesis of Compound 39-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added Anhydrous DMF solution, after which the reaction mixture was warmed to 30°C and stirred for two hours. Then, a solution of compound 39-4 (1.1 g, 3.6 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and the reaction mixture was stirred overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 20 mL of water, washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the combined The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1 ) was purified to give white solid compound 39-5 (1.0 g, yield: 56%)

Step 5: Synthesis of Compound 39-6

Compound 39-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, the reaction mixture was warmed to 30 °C, and stirred for 6 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 39-6 (0.86 g, yield 60%).

Step 6: Synthesis of Compound 39-8

Compound 39-6 (0.91 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 mL of dichloromethane was added, and then Cool to 0°C and add DIPEA (0.6 mL, 3.0 mmol). The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 39-8 (0.92 g, yield 98%).

Step 7: Synthesis of Compound 39-9

Compound 39-8 (0.53 g, 0.58 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C, at this temperature Stir for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a purified white Solid compound 39-9 (0.25 g, yield: 48%).

MS(ESI, pos.ion) m/z: 886.0[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.13 (s, 1H), 9.01 (s, 1H), 7.66-7.57 (m, 1H), 7.26 (d, J=8.5Hz, 1H), 7.20 –7.04(m,3H),6.80–6.69(m,2H),5.81(s,1H),5.61(d,J=7.1Hz,1H),5.07(s,1H),4.58(t,J=15.6 Hz, 1H), 4.54–4.46 (m, 1H), 4.06 (s, 1H), 3.90 (d, J=8.8Hz, 1H), 3.73 (s, 3H), 2.90 (s, 1H), 2.70–2.53 (m, 2H), 2.35(d, J=9.0Hz, 2H), 1.75(d, J=9.0Hz, 2H), 1.59(dd, J=16.8, 9.0Hz, 2H), 1.31(d, J= 40.2Hz,6H),1.28–0.41(m,18H)ppm;

HPLC purity: 95.43%.

Example 40:

synthetic route:

Step 1: Synthesis of Compound 40-2

Compound 40-0 (4.0 g, 12 mmol) and compound 40-1 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, and then the reaction mixture was heated to reflux, and the reaction overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of EtOAc was added, the organic phase was washed with H ₂ O (100 mL×2), washed once with 50 mL of saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and the organic phase was removed under reduced pressure. solvent to obtain a yellow solid 40-2 (4.0 g, yield: 95%), which was directly carried out to the next step without further purification.

Step 2: Synthesis of Compound 40-3

Compound 40-2 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was heated to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100 ml of 1N HCl aqueous solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 40-3 (3.0 g, yield : 91%).

Step 3: Synthesis of Compound 40-4

Compound 40-3 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added mmol), the temperature of the reaction solution was raised to 110°C, and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was cooled to 0°C, 5 mL of water was added to quench the reaction, the organic phase was washed with water (10 mL×2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent to obtain the product 40-4 as a pale yellow solid (1.1 g, 100%), which was directly carried out to the next step without further purification.

Step 4: Synthesis of Compound 40-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added Anhydrous DMF solution, after which the reaction mixture was warmed to 30°C and stirred for two hours. Then, 5 mL of anhydrous tetrahydrofuran solution containing compound 40-4 (1.1 g, 3.6 mmol) was added to the above reaction solution, followed by stirring overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 20 mL of water, washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the combined The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) Purification gave white solid compound 40-5 (1.0 g, yield: 56%).

Step 5: Synthesis of Compound 40-6

Compound 40-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, the reaction mixture was warmed to 30 °C, and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 40-6 (0.86 g, yield 60%).

Step 6: Synthesis of Compound 40-8

Compound 40-6 (0.82 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate, and then dried in vacuo.

The solid obtained from the above reaction, compound 2-11 (0.6g, 1.3mmol), EDCI (0.3g, 2mmol) and HOAT (0.2g, 1mmol) were added to a round-bottomed flask, and 20 ml of dichloromethane were added under nitrogen protection, It was then cooled to 0°C and DIPEA (0.6 mL, 3.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 40-8 (0.92 g, yield 98%).

Step 7: Synthesis of Compound Target 40-9

Compound 40-8 (0.48 g, 0.58 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C and stirred for 48 hours . After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 40 -9 (0.25 g, yield: 48%).

MS(ESI, pos.ion) m/z: 810.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.50 (d, J=91.5 Hz, 1H), 7.20-7.15 (m, 1H), 7.11-7.01 (m, 3H), 7.00 (dd, J=8.6, 2.4Hz, 1H), 6.86(t, J＝6.9Hz, 1H), 5.89(s, 1H), 5.70(dd, J＝17.9, 8.6Hz, 1H), 5.40(t, J＝20.8Hz, 1H) ,4.97(t,J＝9.0Hz,1H),4.66(d,J＝38.8Hz,1H),4.46(dd,J＝54.5,22.1Hz,1H),4.36(d,J＝6.9Hz,1H) ,4.15–4.08(m,1H),4.03(d,J=9.2Hz,1H),3.90(s,3H),2.89(s,1H),2.59(d,J=44.2Hz,3H),2.34( dt, J=14.9, 7.4Hz, 1H), 2.04 (s, 1H), 1.88 (d, J=37.4Hz, 3H), 1.52–1.20 (m, 20H) ppm;

HPLC purity: 93.36%.

Example 41:

synthetic route:

Step 1: Synthesis of Compound 41-2

Compound 41-0 (4.0 g, 12 mmol) and compound 41-1 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, and then the reaction mixture was heated to reflux, and the reaction overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of EtOAc was added, and then washed with H ₂ O (100 mL×2), the organic phase was washed once with 50 mL of saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and dried under reduced pressure. The organic solvent was removed to give 41-2 as a yellow solid (4.0 g, yield: 95%).

Step 2: Synthesis of Compound 41-3

Compound 41-2 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was heated to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the solid was filtered off, the filtrate was poured into 100 ml of 1N HCl solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 41-3 (3.0 g , Yield: 91%).

Step 3: Synthesis of Compound 41-4

Compound 41-3 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to 0°C, 5 mL of water was added to quench the reaction, the organic phase was washed with water (10 mL×2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure , a pale yellow solid compound 41-4 (0.97 g, yield: 100%) was obtained, and the obtained solid was directly subjected to the next reaction without further purification.

Step 4: Synthesis of Compound 41-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 containing compound 2-7 (1.0 g, 4.3 mmol) was added. mL of anhydrous DMF solution, then warmed to 30°C and stirred for two hours. 5 mL of anhydrous tetrahydrofuran solution containing compound 41-4 (1.1 g, 3.6 mmol) was added to the above reaction solution, followed by stirring overnight. After the reaction was completed, the reaction solution was cooled to 0 °C, quenched with 20 mL of water, and then rinsed with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and extracted with ethyl acetate (20 mL × 3 ), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification to obtain white solid compound 41-5 (1.0 g, yield: 56%).

Step 5: Synthesis of Compound 41-6

Compound 41-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, the reaction mixture was warmed to 30 °C, and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with 20 mL of ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 41-6 (0.86 g, yield 60%).

Step 6: Synthesis of Compounds 41-8

Compound 41-6 (0.86 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 20 mL of 30% ethyl acetate solution of hydrochloric acid was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 ml of dichloromethane were added, It was then cooled to 0°C and DIPEA (0.6 mL, 3.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 41-8 (0.92 g, yield 98%).

Step 7: Synthesis of Target 41-9

Compound 41-8 (0.5 g, 0.58 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C and stirred for 48 hours . After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 41 as a white solid -9 (0.25 g, yield: 48%).

MS(ESI, pos.ion) m/z: 810.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.58-10.23 (m, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.16 (dd, J=9.6, 5.9 Hz, 1H), 6.91-6.82 (m, 2H), 6.68 (d, J=7.1Hz, 2H), 5.87 (s, 1H), 5.73 (dd, J=17.9, 8.7Hz, 1H), 5.39–5.08 (m, 1H), 4.98 ( dd,J＝22.7,13.0Hz,1H),4.61(t,J＝7.2Hz,1H),4.51(d,J＝11.1Hz,1H),4.36(t,J＝7.7Hz,1H),4.03( d, J=9.8Hz, 1H), 3.84 (s, 3H), 2.92 (dd, J=12.5, 7.8Hz, 1H), 2.69–2.49 (m, 3H), 2.39–2.27 (m, 1H), 2.12 –1.79(m,4H),1.77(s,3H),1.31(d,J=21.9Hz,19H)ppm;

HPLC purity: 92.14%.

Example 42:

synthetic route:

Step 1: Synthesis of Compound 42-2

Compound 42-0 (2.2 g, 10 mmol), compound 42-1 (1.5 g, 11 mmol), Pd(PPh ₃ ) ₄ (0.35 g, 0.3 mmol) and K ₂ CO ₃ (6.9 g, 50 mmol) were dissolved in THF (60 mL) and water (5 mL) in a mixture solvent, under nitrogen protection, the temperature of the sorted solution was raised to 80°C and stirred overnight. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×50 mL), the organic phases were combined, the extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow Solid compound 42-2 (2.4 g, yield: 96%).

Step 2: Synthesis of Compound 42-4

Compound 42-2 (2.25 g, 9.57 mmol) and compound 42-3 (1.79 g, 13.6 mmol) were dissolved in 15 mL of DMF, and K ₂ CO ₃ (2.64 g, 19.1 mmol) was added thereto, after which the reaction mixture was warmed to Reflux and react overnight. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (100 mL×2), washed with 50 mL of saturated brine once, and the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and reduced in pressure. The organic solvent was removed under low temperature to obtain a yellow solid 42-4 (3.2 g, yield: 87%), which was directly carried out to the next step without further purification.

MS(ESI, pos.ion) m/z: 386[M+H] ⁺ .

Step 3: Synthesis of Compound 42-5

Compound 42-4 (3.2 g, 8.3 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the solid was removed by filtration, the filtrate was poured into 100 ml of 1N HCl solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 42-5 (2.6 g , Yield: 97%).

MS(ESI, pos.ion) m/z: 324.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 42-6

Compound 42-5 (1.0 g, 3.1 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.6 mL, 6.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.16 mL, 1.3 mmol) was slowly added mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, 5 mL of water was added to quench the reaction, the organic phase was washed with water (10 mL×2), washed once with saturated brine, then dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The organic solvent was removed to obtain compound 42-6 as a pale yellow solid (0.75 g, yield: 71%).

MS (ESI, pos.ion) m/z: 342 [M+H] ⁺ .

Step 5: Synthesis of Compound 42-7

Sodium hydride (60% dispersed in mineral oil, 0.26 g, 6.5 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then added with compound 2-7 (0.56 g, 2.4 mmol) 10 mL of anhydrous DMF solution was then warmed to 30°C and stirred for two hours. 5 mL of anhydrous tetrahydrofuran solution containing compound 42-6 (0.75 g, 2.2 mmol) was added to the above reaction solution, and then reacted overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 20 mL of water, and then washed with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, and then extracted with ethyl acetate. (20 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V :V)=2:1) purification to give white solid compound 42-7 (1.2 g, yield: 100%)

MS (ESI, neg.ion) m/z: 535 [MH] ^- .

Step 6: Synthesis of Compound 42-8

Compound 42-7 (1.2 g, 2.2 mmol), compound 1-9 (1.1 g, 2.7 mmol), EDCI (0.56 g, 2.9 mmol) and HOAT (0.37 g, 2.7 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0°C, DIPEA (1.2 mL, 6.9 mmol) was added, and the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and reduced in pressure The organic solvent was removed under low temperature, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 42-8 (1.2 g, yield 72%).

Step 7: Synthesis of Compounds 42-10

Compound 42-8 (1.2 g, 1.6 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. The reaction mixture was filtered and the filter cake was rinsed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 2-11 (0.7 g, 2 mmol), EDCI (0.33 g, 1.7 mmol) and HOAT (0.22 g, 1.6 mmol) were added to a round-bottomed flask, and 20 mL of dichloromethane was added under nitrogen protection. , then cooled to 0 °C, and DIPEA (0.7 mL, 4 mmol) was added. The reaction solution was heated to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 42-10 (0.98 g, yield 80%).

Step 8: Synthesis of Target 42-11

Compound 42-10 (0.4 g, 0.4 mmol) was dissolved in 400 ml of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C, at this temperature Stir for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 42-11 ( 0.24 g, yield: 60%).

MS(ESI, pos.ion) m/z: 874[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.34 (s, 1H), 7.66-7.51 (m, 1H), 7.49-7.42 (m, 1H), 7.41-7.36 (m, 2H), 7.36-7.29 ( m, 2H), 7.22 (t, 1H), 7.20–7.13 (m, 1H), 7.13 (s, 1H), 6.98–6.83 (m, 2H), 5.95 (s, 1H), 5.74 (dd, J= 17.7, 8.7Hz, 1H), 5.21 (d, J=7.4Hz, 1H), 5.01 (t, J=9.4Hz, 1H), 4.75–4.53 (m, 2H), 4.42–4.31 (m, 1H), 4.13–3.98 (m, 1H), 2.93 (s, 1H), 2.74–2.48 (m, 3H), 2.41–2.30 (m, 1H), 1.99–1.69 (m, 6H), 1.45–1.32 (m, 11H) ),1.25–1.04(m,3H),1.00–0.78(m,4H)ppm;

HPLC purity: 96.15%.

Example 43:

synthetic route:

Step 1: Synthesis of Compound 43-2

Compound 43-0 (1.1 g, 5 mmol), compound 43-1 (1.0 g, 5 mmol), Pd(PPh ₃ ) ₄ (0.17 g, 0.15 mmol) and K ₂ CO ₃ (3.5 g, 25 mmol) were added to THF In a mixed solvent of (60 mL) and water (15 mL), under nitrogen protection, the reaction mixture was warmed to reflux and stirred overnight. After the reaction was completed, saturated sodium chloride solution (100 mL) was added to quench, then extracted with ethyl acetate (3×50 mL), the extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure A yellow solid compound 43-2 was obtained (1.3 g, yield: 89%).

Step 2: Synthesis of Compound 43-4

Compound 43-2 (1.32 g, 4.46 mmol) and compound 43-3 (0.76 g, 4.5 mmol) were dissolved in 20 mL of DMF, K ₂ CO ₃ (1.3 g, 9.3 mmol) was added, and then the reaction mixture was heated to reflux, and the reaction overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of EtOAc was added, washed with H ₂ O (100 mL×2), and washed once with 50 mL of saturated brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and the organic solvent was removed under reduced pressure to obtain a yellow solid 43-4 (0.94 g, yield: 47%), which was directly carried out to the next step without further purification.

MS(ESI, pos.ion) m/z: 446[M+H] ⁺ .

Step 3: Synthesis of Compound 43-5

Compound 43-4 (0.94 g, 2.1 mmol) was dissolved in 15 mL of glacial acetic acid, then reduced iron powder (0.6 g, 10 mmol) was added, and the reaction mixture was heated to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered to remove the solid, the filtrate was poured into 50 ml of 1N HCl solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 43-5 (0.8 g, yield : 99%). MS(ESI, pos.ion) m/z: 384[M+H] ⁺ .

Step 4: Synthesis of Compound 43-6

Compound 43-5 (0.94 g, 2.4 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.45 mL, 4.9 mmol) was added under nitrogen protection, and N,N-dimethylaniline (0.12 mL, 0.98 mmol) was added slowly mmol), the temperature was raised to 110 °C, and the reaction was carried out for 6 hours. After the reaction was completed, the reaction solution was cooled to 0°C, 5 mL of water was added to quench the reaction, the organic phase was washed with water (10 mL×2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure , the compound 43-6 was obtained as a pale yellow solid (0.68 g, yield: 69%).

Step 5: Synthesis of Compound 43-7

Sodium hydride (60% dispersed in mineral oil, 0.2 g, 5 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (0.43 g, 1.9 mmol) was added Anhydrous DMF solution, the reaction mixture was then warmed to 30°C and stirred for two hours. Then, 5 mL of anhydrous tetrahydrofuran solution containing compound 43-6 (0.68 g, 1.7 mmol) was added to the above reaction solution, and then reacted overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 20 mL of water, and then washed with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 43-7 (1.0 g, yield: 99%)

MS (ESI, neg.ion) m/z: 595 [MH] ^- .

Step 6: Synthesis of Compound 43-8

Compound 43-7 (1.0 g, 1.7 mmol), compound 1-9 (0.81 g, 2.0 mmol), EDCI (0.43 g, 2.2 mmol) and HOAT (0.27 g, 2.0 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0 °C, DIPEA (0.9 mL, 5 mmol) was added, the reaction mixture was warmed to 30 °C, and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 43-8 (0.9 g, yield 70%).

MS (ESI, pos.ion) m/z: 809 [M+H] ⁺ .

Step 7: Synthesis of Compound 43-10

Compound 43-8 (0.9 g, 1 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no gas The reaction was terminated when released. The reaction mixture was filtered and the resulting white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 2-11 (0.54 g, 1.2 mmol), EDCI (0.25 g, 1.3 mmol) and HOAT (0.17 g, 1.2 mmol) were added to a round-bottomed flask, and 20 mL of dichloride was added under nitrogen protection. Methane, then cooled to 0°C, DIPEA (0.52 mL, 3 mmol) was added, after which the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 43-10 (0.78 g, yield 82%).

Step 8: Synthesis of Compounds 43-11

Compound 43-10 (0.5 g, 0.5 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 65 °C and stirred for 48 hours . The reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 43-11 (0.17 g, yield: 40%).

MS(ESI, pos.ion) m/z: 934[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.36 (s, 1H), 7.70 (m, 1H), 7.63–7.50 (m, 1H), 7.40–7.31 (m, 2H), 7.31–7.18 (m, 5H), 6.97–6.84 (m, 2H), 5.94 (s, 1H), 5.73 (dd, J=17.7, 8.7Hz, 1H), 5.25 (d, J=7.3Hz, 1H), 5.07–4.96 (m ,1H),4.80–4.49(m,2H),4.40–4.29(m,1H),4.12–4.00(m,1H),2.93(s,1H),2.74–2.50(m,3H),2.40–2.29 (m, 1H), 2.00–1.72 (m, 6H), 1.49–1.33 (m, 11H), 1.22–1.07 (m, 3H), 0.98–0.83 (m, 4H) ppm;

HPLC purity: 97.29%.

Example 44:

synthetic route:

Step 1: Synthesis of Compound 44-3

Compound 9-10 (0.11 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate, and compound 44-1 was dried in vacuo.

The compound 44-1, compound 44-2 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, and 20 mL was added under nitrogen protection Dichloromethane was then cooled to 0°C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 44-3 (0.70 g, yield 59%).

MS(ESI, pos.ion) m/z: 789.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.40 (s, 1H), 7.97 (d, J=5.9 Hz, 1H), 7.70 (s, 1H), 7.55-7.44 (m, 1H), 7.30-7.26 (m,1H),7.20–7.11(m,3H),6.91(d,J=7.3Hz,1H),6.78(t,J=7.3Hz,1H),6.19(s,1H),5.95(s, 1H), 5.75(d, J＝8.5Hz, 1H), 5.00(t, J＝8.7Hz, 1H), 4.83(d, J＝7.4Hz, 1H), 4.71–4.55(m, 2H), 4.12( d, J=7.9Hz, 1H), 2.92(s, 1H), 2.66(s, 3H), 2.41(s, 3H), 2.35-2.26(m, 1H), 2.20-2.08(m, 1H), 2.02 –1.60(m,7H),1.46–1.38(m,3H),0.94–0.79(m,4H)ppm;

HPLC purity: 92.01%.

Example 45:

synthetic route:

Step 1: Synthesis of Compound 45-3

Compound 9-10 (0.12 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the filter cake was washed with 20 mL of ethyl acetate to obtain compound 45-1.

Compound 45-1, compound 45-2 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) obtained above were added to a round-bottomed flask, under nitrogen protection, 20 mL was added Dichloromethane was then cooled to 0°C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 45-3 (0.11 g, yield 93%).

MS(ESI, pos.ion) m/z: 786[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.32(s, 1H), 9.21(s, 1H), 8.73(s, 1H), 8.54(s, 1H), 8.22(d, J=7.1Hz, 1H ),7.58(dd,J=8.3,6.6Hz,1H),7.27-7.23(m,1H),7.22-7.12(m,4H),6.95-6.77(m,2H),5.95(s,1H), 5.76(dd,J＝17.8,8.6Hz,1H),5.02(t,J＝9.4Hz,1H),4.79(t,J＝7.0Hz,1H),4.61(t,J＝7.7Hz,1H), 4.55(d, J=11.4Hz, 1H), 4.19–4.10 (m, 1H), 2.97–2.88 (m, 1H), 2.66–2.51 (m, 3H), 2.33 (q, J=8.6Hz, 1H) ,2.11–2.04(m,1H),1.99–1.90(m,2H),1.83–1.62(m,5H),1.41–1.31(m,3H),1.01–0.80(m,4H)ppm;

HPLC purity: 97.15%.

Example 46:

synthetic route:

Step 1: Synthesis of Compound 46-2

Compound 25-10 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the filter cake was washed with 20 mL of ethyl acetate, and then dried under vacuum to give compound 46-0.

Compound 46-0, compound 46-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) obtained above were added to a round-bottomed flask, and under nitrogen protection, 20 mL of dichloromethane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 46-2 (0.09 g, yield 75%).

MS(ESI, pos.ion) m/z: 847[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.40 (s, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.74 (s, 1H), 7.46 (dd, J=8.2, 6.7 Hz, 1H ), 7.15(d, J=8.7Hz, 1H), 6.87(dd, J=8.8, 1.7Hz, 1H), 6.81–6.65(m, 3H), 6.19(s, 1H), 5.90(d, J= 2.3Hz, 1H), 5.75(dd, J＝17.6, 8.8Hz, 1H), 5.00(t, J＝9.3Hz, 1H), 4.82(t, J＝8.0Hz, 1H), 4.65(t, J＝ 7.7Hz, 1H), 4.60 (d, J=11.4Hz, 1H), 4.51 (dt, J=12.0, 6.0Hz, 1H), 4.10 (dd, J=11.3, 3.8Hz, 1H), 2.99–2.86 ( m, 1H), 2.65 (d, J=4.3Hz, 3H), 2.42 (s, 3H), 2.31 (q, J=8.4Hz, 1H), 2.21–2.10 (m, 1H), 1.97–1.61 (m ,7H),1.37–1.31(m,9H),

0.94–0.80(m,4H)ppm;

HPLC purity: 94.80%.

Example 47:

synthetic route:

Step 1: Synthesis of Compound 47-2

Compound 25-10 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the filter cake was rinsed with 20 mL of ethyl acetate to obtain compound 47-0.

The above compound 47-0, compound 47-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 mL of Chloromethane was then cooled to 0°C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 47-2 (0.075 g, yield 63%).

MS(ESI, pos.ion) m/z: 844[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ): δ 10.33(s, 1H), 9.22(s, 1H), 8.72(s, 1H), 8.54(s, 1H), 8.24(d, J=6.7Hz, 1H ),7.65–7.52(m,1H),7.28(s,1H),7.14(d,J=8.5Hz,1H),6.91–6.79(m,2H),6.76–6.65(m,2H),5.90( s, 1H), 5.75(dd, J=17.4, 8.6Hz, 1H), 5.01(t, J=9.2Hz, 1H), 4.80(s, 1H), 4.60(t, J=7.4Hz, 1H), 4.55–4.43 (m, 2H), 4.13 (d, J=7.8Hz, 1H), 2.92 (s, 1H), 2.56 (s, 3H), 2.38–2.27 (m, 1H), 2.10–2.03 (m, 1H), 2.01–1.88 (m, 3H), 1.85–1.71 (m, 4H), 1.57–1.40 (m, 9H), 0.96–0.82 (m, 4H) ppm;

HPLC purity: 95.90%.

Example 48:

synthetic route:

Step 1: Synthesis of Compound 48-3

Compound 11-12 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the filter cake was rinsed with 20 mL of ethyl acetate to obtain compound 48-1 as a white solid.

Compound 48-1, compound 48-2 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) obtained above were added to a round-bottomed flask, under nitrogen protection, 20 mL was added Dichloromethane was then cooled to 0°C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 48-3 (0.11 g, yield 83%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.37 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.46(dd,J=7.7,1.3Hz,1H),7.44-7.39(m,1H),7.37(dt,J=4.4,2.1Hz,2H),7.32-7.29(m,1H),7.20(d, J=8.0Hz, 1H), 7.05(t, J=7.5Hz, 1H), 6.99(d, J=8.7Hz, 2H), 6.17(s, 1H), 5.97(d, J=3.2Hz, 1H) , 5.83–5.68 (m, 1H), 5.06–4.96 (m, 1H), 4.92–4.78 (m, 1H), 4.66 (dd, J=13.9, 6.0Hz, 2H), 4.13 (dd, J=11.5, 4.1Hz, 1H), 3.87 (s, 3H), 3.00–2.85 (m, 1H), 2.73–2.59 (m, 3H), 2.40 (s, 3H), 2.34 (q, J=8.8Hz, 1H), 1.96-1.87(m,2H),1.56-1.50(m,3H),1.33-1.29(m,3H),1.19-1.10(m,3H),0.96-0.89(m,4H)ppm;

HPLC purity: 99.14%.

Example 49:

synthetic route:

Step 1: Synthesis of Compound 49-1

Compound 49-0 (2.0 g, 12.7 mmol), isopropanol (0.786 g, 13.1 mmol), diphenyl-2-pyridinephosphine (DPPPy, 5.0 g, 19.0 mmol) and di-tert-butyl azodicarboxylate were combined (DBAD, 4.4 g, 19.0 mmol) was dissolved in 100 mL of THF, and the reaction solution was stirred at room temperature under nitrogen protection for 24 hours. After the reaction, the organic solvent was removed under reduced pressure, the obtained residue was dissolved in 30 mL of ethyl acetate, then washed with 20 mL of 1N HCl solution, the separated organic phase was dried over anhydrous Na ₂ SO ₄ , and the organic solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow oily product 49-1 (2.46 g, yield: 97%)

Step 2: Synthesis of Compound 49-3

Compound 49-1 (4.0 g, 12 mmol) and compound 49-2 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, and K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, after which the reaction mixture was warmed to reflux, React overnight. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (100 mL×2), washed with 50 mL of saturated brine once, and the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and washed under reduced pressure. The organic solvent was removed to obtain a yellow solid 49-3 (4.0 g, yield: 95%), which was directly carried out to the next step without further purification

MS (ESI, pos.ion) m/z: 350 [M+H] ⁺ .

Step 3: Synthesis of Compound 49-4

Compound 49-3 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, and the solid was removed by filtration. The filtrate was poured into 100 mL of 1N HCl solution, and a large amount of white solid was precipitated. : 91%).

MS(ESI, pos.ion) m/z: 288[M+H] ⁺ .

Step 4: Synthesis of Compound 49-5

Compound 49-4 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. After the reaction was completed, it was cooled to 0°C, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 49- 5 (1.1 g, 100%).

MS(ESI, pos.ion) m/z: 306[M+H] ⁺ .

Step 5: Synthesis of Compound 49-6

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0°C under nitrogen protection, and then 10 mL of compound 2-7 (1.0 g, 4.3 mmol) was added Anhydrous DMF solution was then warmed to 30°C and stirred for two hours. 5 mL of anhydrous tetrahydrofuran solution containing compound 49-5 (1.1 g, 3.6 mmol) was added to the above reaction solution, followed by stirring overnight. After the reaction was completed, the reaction solution was cooled to 0°C, then quenched with 20 mL of water, washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, and extracted with ethyl acetate (20 mL×3 ), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification to obtain white solid compound 49-6 (1.0 g, yield: 56%).

MS (ESI, pos.ion) m/z: 501 [M+H] ⁺ .

Step 6: Synthesis of Compound 49-7

Compound 49-6 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, the reaction mixture was warmed to 30 °C, and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain purified white solid compound 49-7 (0.86 g, yield 60%).

MS (ESI, pos.ion) m/z: 713 [M+H] ⁺ .

Step 7: Synthesis of Compound 49-9

Compound 49-7 (0.86 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 20 mL of 30% ethyl acetate solution of hydrochloric acid was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the filter cake was rinsed with 20 mL of ethyl acetate to obtain compound 49-8.

Compound 49-8, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) obtained above were added to a round-bottomed flask, and 20 mL of dichloride was added under nitrogen protection. Methane, then cooled to 0 °C and DIPEA (0.6 mL, 3.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 49-9 (0.92 g, yield 98%). MS(ESI, pos.ion) m/z: 866[M+H] ⁺ .

Step 8: Synthesis of Compounds 49-10

Compound 49-9 (0.5 g, 0.58 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 65 °C and stirred for 48 hours . After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 49 as a white solid -10 (0.25 g, yield: 48%).

MS(ESI, pos.ion) m/z: 838[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 7.61-7.49 (m, 1H), 7.14 (s, 1H), 7.02 (d, J=8.8Hz, 1H), 6.91-6.80 (m, 2H), 6.74 (s, 1H), 6.69–6.62 (m, 1H), 5.91 (s, 1H), 5.72 (d, J=9.2Hz, 1H), 5.24 (d, J=7.3Hz, 1H), 5.07–4.96 ( m, 1H), 4.73–4.57 (m, 1H), 4.57–4.45 (m, 2H), 4.39–4.31 (m, 1H), 4.11–4.00 (m, 1H), 2.96–2.90 (m, 1H), 2.70–2.51 (m, 3H), 2.39–2.27 (m, 1H), 2.01–1.72 (m, 5H), 1.60 (s, 2H), 1.51–1.42 (m, 6H), 1.32–1.23 (m, 11H) ),1.21–1.02(m,3H),1.06–0.77(m,4H)ppm;

HPLC purity: 96.88%.

Example 50:

synthetic route:

Step 1: Synthesis of Compound 50-1

Compound 50-0 (0.9 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (petroleum ether) to obtain a pale yellow solid product 50-1 (0.7 g, 72%).

MS (ESI, pos.ion) m/z: 278 [M+H] ⁺ .

Step 2: Synthesis of Compound 50-2

Sodium hydride (60% dispersed in mineral oil, 0.15 g, 3.8 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then added with compound 2-7 (0.42 g, 1.8 mmol). 10 mL of anhydrous DMF solution, after which the reaction mixture was warmed to 30°C and stirred for two hours. Then, 5 mL of anhydrous tetrahydrofuran solution containing compound 50-1 (0.44 g, 1.6 mmol) was added to the above reaction solution, and then reacted overnight. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 20 mL of water, washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20 mL × 3 ), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification to obtain compound 50-2 as a white solid (0.4 g, yield: 53%).

Step 3: Synthesis of Compound 50-3

Compound 50-2 (0.94 g, 2 mmol), compound 1-9 (0.68 g, 1.7 mmol), EDCI (0.4 g, 2 mmol) and HOAT (0.3 g, 2 mmol) were added to a round-bottomed flask, and added under nitrogen protection 30 mL of dichloromethane was then cooled to 0 °C, DIPEA (0.8 mL, 5 mmol) was added and the reaction mixture was warmed to 30 °C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 50-3 (0.95 g, yield 69%).

MS(ESI, pos.ion) m/z: 685[M+H] ⁺ .

Step 4: Synthesis of Compound 50-5

Compound 50-3 (0.87 g, 1.28 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 20 mL of 30% ethyl acetate solution of hydrochloric acid was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the filter cake was washed with 20 mL of ethyl acetate to obtain compound 50-4 as a white solid.

Compound 50-4, compound 2-11 (0.7 g, 1.55 mmol), EDCI (0.32 g, 1.7 mmol) and HOAT (0.21, 1.5 mmol) obtained above were added to a round-bottomed flask, under nitrogen protection, 20 mL of two Chloromethane was then cooled to 0°C and DIPEA (0.7 mL, 4 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 50-5 (0.75 g, yield 70%).

MS (ESI, neg.ion) m/z: 838 [MH] ^- .

Step 5: Synthesis of Target 50-6

Compound 50-5 (0.15 g, 0.18 mmol) was dissolved in 400 ml of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C, at this temperature Stir for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 50 -6 (80 mg, yield: 54%).

MS(ESI, pos.ion) m/z: 798[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62-7.41 (m, 1H), 7.20-7.01 (m, 2H), 6.92-6.84 (m, 2H), 6.81-6.73 (m, 2H), 5.97 ( s, 1H), 5.72(d, J=9.3Hz, 1H), 5.23(d, J=7.1Hz, 1H), 5.01(t, J=9.4Hz, 1H), 4.83–4.42(m, 2H), 4.42–4.32 (m, 1H), 4.17–4.01 (m, 1H), 3.89 (s, 3H), 2.96–2.90 (m, 1H), 2.69–2.50 (m, 3H), 2.34–2.25 (m, 1H) ), 2.01–1.72 (m, 5H), 1.67–1.59 (m, 1H), 1.39–1.33 (m, 11H), 1.22–1.03 (m, 4H), 0.91–0.83 (m, J=6.5Hz, 4H )ppm;

HPLC purity: 94.12%.

Example 51:

synthetic route:

Step 1: Synthesis of Compound 51-2

Compound 49-10 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the filter cake was washed with 20 mL of ethyl acetate to obtain compound 51-0 as a white solid.

Compound 51-0, compound 51-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, and 20 mL of dichloride was added under nitrogen protection Methane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction solution was heated to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 51-2 (0.075 g, yield 63%).

MS(ESI,neg.ion)m/z:856[MH] ^- ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.36(s,1H), 9.08(s,1H), 8.42(s,1H), 8.16(s,1H), 7.61-7.52(m,2H), 7.02 (d,J=8.8Hz,1H),6.87–6.73(m,3H),6.65(dd,J=8.8,2.9Hz,1H),5.93(s,1H),5.75(d,J=9.3Hz, 1H), 5.04–4.98 (m, 1H), 4.74 (t, J=6.7Hz, 1H), 4.59 (t, J=7.6Hz, 1H), 4.55–4.44 (m, 2H), 4.19–4.11 (m , 1H), 2.96–2.86 (m, 1H), 2.63 (s, 3H), 2.60–2.42 (m, 3H), 2.30 (q, J=8.5Hz, 1H), 2.09–2.02 (m, 1H), 1.97–1.89 (m, 3H), 1.82–1.74 (m, 1H), 1.68–1.59 (m, 1H), 1.58–1.42 (m, 6H), 1.37–1.34 (m, 2H), 1.20–1.04 (m ,3H),1.06–0.63(m,4H)ppm;

HPLC purity: 95.29%.

Example 52:

synthetic route:

Step 1: Synthesis of Compound 52-2

Compound 49-10 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction was terminated when gas evolved. After filtration, the filter cake was rinsed with 20 mL of ethyl acetate to obtain compound 52-0 as a white solid.

Compound 52-0, compound 52-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round bottom flask, under nitrogen protection, 20 mL of dichloromethane was added Methane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 52-2 (0.09 g, yield 75%).

MS(ESI, pos.ion) m/z: 847[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.39 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 7.47 (dd, J=8.6, 6.4 Hz, 1H), 7.02 (d ,J=7.6Hz,1H),6.88(dd,J=9.0,2.3Hz,1H),6.82-6.72(m,2H),6.66(dd,J=8.8,2.9Hz,1H),6.21(s, 1H), 5.93(d, J＝3.1Hz, 1H), 5.75(dd, J＝17.8, 8.9Hz, 1H), 5.00(t, J＝9.3Hz, 1H), 4.89–4.77(m, 1H), 4.71–4.58 (m, 2H), 4.57–4.48 (m, 1H), 4.10 (dd, J=11.5, 4.1Hz, 1H), 2.98–2.85 (m, 1H), 2.77–2.58 (m, 3H), 2.42(s, 3H), 2.31(q, J=8.5Hz, 1H), 2.21-2.12(m, 1H), 1.92-1.83(m, 3H), 1.74-1.65(m, 1H), 1.37-1.30( m, 9H), 1.22–1.01 (m, 3H), 1.02–0.74 (m, 4H) ppm;

HPLC purity: 95.17%.

Example 53:

synthetic route:

Step 1: Synthesis of Compound 53-2

Compound 26-11 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the filter cake was rinsed with 20 mL of ethyl acetate to obtain compound 53-0 as a white solid.

Compound 53-0, compound 53-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, and 20 mL of dichloride was added under nitrogen protection Methane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) gave compound 53-2 as a white solid (0.070 g, yield 52%).

MS(ESI,neg.ion)m/z:883.8[MH] ^- ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.34 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 8.15 (d, J=6.9 Hz, 1H), 7.62 (dd, J =8.5,6.4Hz,1H),7.48(s,1H),7.27–7.22(m,1H),7.10–6.99(m,2H),6.95–6.82(m,2H),5.92(s,1H), 5.81–5.70 (m, 1H), 5.07–4.95 (m, 1H), 4.78–4.68 (m, 1H), 4.63–4.47 (m, 2H), 4.20–4.10 (m, 1H), 2.97–2.83 (m ,1H),2.66–2.50(m,6H),2.37–2.25(m,1H),2.05–1.80(m,5H),1.53–1.48(m,3H),1.17–1.06(m,3H),0.92 –0.84(m,4H)ppm;

HPLC purity: 92.49%.

Example 54:

synthetic route:

Step 1: Synthesis of Compound 54-3

Compound 11-12 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then 20 mL of a 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature until The reaction ends when no gas is evolved. After filtration, the filter cake was washed with 20 mL of ethyl acetate to obtain compound 54-1 as a white solid.

Compound 54-1, compound 54-2 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round bottom flask, under nitrogen protection, 20 mL of dichloromethane was added Methane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. The temperature was raised to 30°C, and the mixture was stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 54-3 (0.10 g, yield 75%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.34 (s, 1H), 9.10 (s, 1H), 8.42 (s, 1H), 8.17 (d, J=6.9 Hz, 1H), 7.64-7.58 (m ,1H),7.53(d,J=8.7Hz,2H),7.46(s,1H),7.37(t,J=9.0Hz,3H),7.30–7.28(m,1H),7.22–7.08(m, 2H), 6.98(d, J=8.7Hz, 2H), 5.97(s, 1H), 5.76(d, J=9.5Hz, 1H), 5.03(t, J=9.4Hz, 1H), 4.78(s, 1H), 4.63–4.49 (m, 2H), 4.22–4.12 (m, 1H), 3.86 (s, 3H), 3.00–2.86 (m, 1H), 2.63 (s, 3H), 2.60–2.51 (m, 2H), 2.37–2.27 (m, 1H), 2.12–2.04 (m, 1H), 1.99–1.91 (m, 2H), 1.85–1.70 (m, 3H), 1.41–1.33 (m, 3H), 1.19– 1.08(m,3H),0.98–0.89(m,4H)ppm;

HPLC purity: 98.98%.

Example 55:

synthetic route:

Step 1: Synthesis of Compound 55-2

Compound 26-11 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the filter cake was rinsed with 20 mL of ethyl acetate to obtain compound 55-0 as a white solid.

Compound 55-0, compound 55-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round bottom flask, under nitrogen protection, 20 mL of dichloromethane was added Methane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 55-2 (0.07 g, yield 75%). MS(ESI, pos.ion) m/z: 873.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.35 (s, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.53 (t, J=7.4 Hz, 2H), 7.30-7.23 (m, 2H) ), 7.06(d, J=9.3Hz, 2H), 6.92(dd, J=8.8, 2.1Hz, 1H), 6.89–6.76(m, 1H), 6.21(s, 1H), 5.93(d, J= 2.6Hz, 1H), 5.82–5.71 (m, 1H), 5.06–4.95 (m, 1H), 4.79 (t, J=7.6Hz, 1H), 4.70–4.56 (m, 2H), 4.11 (dd, J = 11.4, 4.2Hz, 1H), 2.99–2.85 (m, 1H), 2.74–2.60 (m, 3H), 2.44 (s, 3H), 2.36–2.27 (m, 1H), 2.16–2.06 (m, 1H) ), 1.94–1.85 (m, 2H), 1.52–1.47 (m, 4H), 1.18–1.08 (m, 3H), 0.97–0.87 (m, 4H) ppm;

HPLC purity: 98.44%.

Example 56

synthetic route

Step 1: Synthesis of Compound 56-2

Compound 56-1 (944 mg, 3.1 mmol) was added to toluene (100 mL), POCl ₃ (939 mg, 6.1 mmol) and N,N-dimethylaniline (185 mg, 1.5 mmol) were slowly added under stirring, after the addition The reaction mixture was heated and refluxed for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain compound 56-2 (0.8 g, yield: 80%) as a light yellow solid after purification.

Step 2: Synthesis of Compound 56-3

Compound N-Boc-4-(R)-hydroxyproline (1.5 g, 6.5 mmol) was dissolved in DMF (50 mL), NaH (60% dispersed in mineral oil, 520 mg, 13 mmol) was added under ice bath, After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. Compound 56-2 (2.1 g, 6.5 mmol) was dissolved in a small amount of DMF, then added to the above reaction solution, and stirring was continued for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, and the pH value was adjusted to 2-3 with 1N HCl solution, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride. The solution was washed, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 56 as a pale yellow solid -3 (3.0 g, yield: 90%).

MS (ESI, neg.ion) m/z: 518.9 [MH] ^- .

Step 3: Synthesis of Compound 56-5

Compound 56-3 (100 mg, 0.19 mmol), compound 56-4 (31 mg, 0.2 mmol), Pd(PPh ₃ ) ₄ (22 mg, 0.02 mmol) and K ₂ CO ₃ (180 mg, 0.58 mmol) were dissolved in THF ( 20 mL) and water (0.1 mL), the reaction mixture was stirred at room temperature overnight under nitrogen protection. After the reaction, saturated sodium chloride solution (20 mL) was added to quench the reaction, then extracted with ethyl acetate (3×10 mL), the organic phases were combined, the extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain yellow solid compound 56-5 (90 mg, yield: 86%).

MS (ESI, pos.ion) m/z: 549.0 [M+H] ⁺ .

Step 4: Synthesis of Compound 56-6

Compound 56-5 (55 mg, 0.1 mmol), compound 1-9 (42 mg, 0.1 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to _{CH2Cl2 (} 15 mL) under nitrogen Under protection, DIPEA (48 mg, 0.37 mmol) was added in an ice bath. After the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, adjust the pH value to about 2 with 1N hydrochloric acid solution, then extract with dichloromethane (10ml×2), combine the organic phases, then wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, spin under reduced pressure The organic solvent was dried, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 56-6 as a pale yellow solid (50 mg, yield: 70%).

Step 5: Synthesis of Compound 56-8

Compound 56-6 (580 mg, 0.76 mmol) was dissolved in 5N HCl ethyl acetate solution (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction, the organic solvent was evaporated under reduced pressure to obtain compound 56-7 as a white solid. The resulting white solid compound (314 mg, 0.45 mmol) was added to CH ₂ Cl ₂ (50 mL), followed by compound 2-11 (223 mg, 0.49 mmol), EDCI (103 mg, 0.54 mmol) and HOAT (73 mg, 0.54 mmol) , DIPEA (177 mg, 1.3 mmol) was added under ice bath, and then the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL×2), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure. The obtained The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 56-8 as a pale yellow solid (0.34 g, yield: 80%).

Step 6: Synthesis of Compound 56-9

Compound 56-8 (453 mg, 0.5 mmol) was dissolved in 1,2-dichloroethane (300 mL), then Jans 1B catalyst (45 mg) was added, and the reaction mixture was heated to 75° C. under nitrogen protection for 48 hours. After the completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 56-9 as a white solid (0.3 g, yield: 70%).

Step 7: Synthesis of Compounds 56-10

Compound 56-9 (339 mg, 0.38 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a white solid compound 56-10 (0.29 g, yield: 90%).

Step 8: Synthesis of Compounds 56-12

Compound 56-10 (110 mg, 0.13 mmol) was dissolved in _{CH2Cl2 (} 50 mL), then compound 56-11 (20 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) and HOAT (22 mg, 0.17 mmol) were added , DIPEA (54 mg, 0.42 mmol) was added under ice bath, and then the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL×2), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure. The obtained The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 56-12 as a pale yellow solid (0.1 g, yield: 80%).

MS(ESI, pos.ion) m/z: 895.3 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.45 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.88 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.49(dd,J＝8.5,6.5Hz,1H),7.45(d,J＝2.1Hz,1H),7.32(dd,J＝8.3,2.1Hz,1H),7.18(d,J＝8.3Hz,1H) ),6.98(d,J＝8.7Hz,2H),6.92(dd,J＝8.9,2.2Hz,1H),6.78(td,J＝8.5,2.2Hz,1H),6.20(s,1H),5.97 (s, 1H), 5.75 (dd, J=17.8, 8.8Hz, 1H), 5.05–4.95 (m, 1H), 4.91–4.78 (m, 1H), 4.68 (dd, J=14.7, 7.1Hz, 2H) ), 4.14–4.08 (m, 1H), 3.85 (s, 3H), 2.97–2.88 (m, 1H), 2.67 (dd, J=17.1, 9.0Hz, 3H), 2.40 (d, J=10.8Hz, 3H), 2.33 (q, J=8.6Hz, 1H), 2.18 (d, J=11.9Hz, 1H), 1.91–1.80 (m, 2H), 1.67 (dd, J=16.2, 7.6Hz, 1H), 1.48 (ddd, J=13.1, 11.9, 8.0Hz, 5H), 1.35–1.27 (m, 4H), 1.12 (ddd, J=13.1, 10.0, 6.2Hz, 2H), 0.93 (dd, J=12.9, 7.6 Hz,1H)ppm;

HPLC purity: 93.00%.

Example 57

synthetic route

Step 1: Synthesis of Compound 57-1

Compound 27-6 (0.20 g, 2.5 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 20 mL of 30% ethyl acetate solution of hydrochloric acid was added, and the reaction mixture was warmed to room temperature and stirred until no more The reaction ends when the gas evolves. After filtration, the filter cake was washed with 20 mL of ethyl acetate, and the resulting solid was dried in vacuo to give a white solid compound. The resulting white compound was added to a round bottom flask with 2-carboxy-5-methylpyrazine (0.4 g, 2.8 mmol), EDCI (0.4 g, 2.6 mmol) and HOAT (0.35 g, 2.7 mmol) under nitrogen protection 20 mL of dichloromethane was added at the bottom, then cooled to 0 °C and DIPEA (1.2 mL, 6.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 57-1 (0.16 g, yield: 78%).

MS(ESI, pos.ion) m/z: 818.4[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 9.04 (s, 1H), 8.41 (s, 1H), 8.17 (d, J=6.4Hz, 1H), 7.63 (dd, J=34.3, 27.3Hz, 2H) ),7.08(dd,J=8.1,5.2Hz,1H),6.94(d,J=7.2Hz,1H),6.90–6.78(m,3H),5.91(s,1H),5.73(dd,J= 17.2, 8.4Hz, 1H), 5.00(t, J＝9.2Hz, 1H), 4.73(s, 1H), 4.61(t, J＝7.2Hz, 1H), 4.51(d, J＝11.1Hz, 1H) ,4.13(dd,J＝23.4,16.0Hz,1H),2.90(s,1H),2.65-2.48(m,6H),2.29(dd,J＝16.5,8.1Hz,1H),2.11-1.99(m ,3H),1.91(d,J＝6.0Hz,2H),1.77(s,1H),1.67–1.57(m,1H),1.34(s,3H),1.17–1.04(m,3H),0.97– 0.77(m,3H)ppm.

Example 58

synthetic route

Step 1: Synthesis of Compound 58-2

Compound 58-0 (4.0 g, 12 mmol) and compound 58-1 (2.31 g, 13.6 mmol) were dissolved in 15 mL of DMF, and K ₂ CO ₃ (3.41 g, 24.7 mmol) was added thereto, after which the reaction mixture was warmed to Reflux and react overnight. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 100 mL of ethyl acetate, and the obtained organic phase was washed with H ₂ O (100 mL×2), washed once with 50 mL of saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and reduced The organic solvent was removed under pressure to obtain yellow solid compound 58-2 (4.0 g, yield: 95%).

MS(ESI, pos.ion) m/z: 336[M+H] ⁺ .

Step 2: Synthesis of Compound 58-3

Compound 58-2 (4.0 g, 11.45 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was poured into 100 mL of 1N HCl solution, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain a white solid compound 58-3 (3.0 g, yield: 91%).

Step 3: Synthesis of Compound 58-4

Compound 58-3 (1.0 g, 3.5 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol), the reaction mixture was warmed to 110°C and reacted for 6 hours. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 58-4 (1.1 g, yield: 100%).

Step 4: Synthesis of Compound 58-5

Sodium hydride (0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 mL of anhydrous DMF solution containing compound 2-7 (1.0 g, 4.3 mmol) was added, and then the reaction was carried out. The mixture was warmed to 30°C and stirred for two hours. 5 mL of anhydrous tetrahydrofuran solution containing compound 58-4 (1.1 g, 3.6 mmol) was added to the above reaction solution, and then reacted overnight. The reaction was quenched with 20 mL of water at 0°C, then washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL x 3), the organic phases were combined and then washed with Washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid Compound 58-5 (1.0 g, yield: 56%).

MS (ESI, pos.ion) m/z: 487.4 [M+H] ⁺ .

Step 5: Synthesis of Compound 58-6

Compound 58-5 (1.0 g, 2.0 mmol), compound 1-9 (0.9 g, 2.0 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen Protected, 30 mL of dichloromethane was added, then cooled to 0 °C, DIPEA (1.05 mL, 6.02 mmol) was added, and the reaction mixture was warmed to 30 °C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 58-6 (0.86 g, yield: 60%).

MS (ESI, pos.ion) m/z: 699.3 [M+H] ⁺ .

Step 6: Synthesis of Compound 58-8

Compound 58-6 (0.86 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the obtained white solid was washed with 20 mL of ethyl acetate, and the obtained solid was dried in vacuo to obtain compound 58-7 as a white solid.

Compound 58-7, compound 2-11 (0.6 g, 1.3 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, and 20 mL of dichloromethane was added under nitrogen protection, It was then cooled to 0°C and DIPEA (0.6 mL, 3.0 mmol) was added slowly. The reaction mixture was then warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 58-8 (0.92 g, yield: 98%). MS (ESI, pos.ion) m/z: 852.3 [M+H] ⁺ .

Step 7: Synthesis of Compound 58-9

Compound 58-8 (0.5 g, 0.58 mmol) was dissolved in 400 ml of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C, at this temperature Stir for 48 hours. Cooled to room temperature, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 58-9 (0.25 g, yield rate: 48%).

MS (ESI, pos.ion) m/z: 824.3 [M+H] ⁺ .

Step 8: Synthesis of Compounds 58-10

Compound 58-9 (0.20 g, 2.5 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the filter cake was washed with 20 mL of ethyl acetate and the resulting white solid was dried in vacuo.

The white solid obtained above, 2-carboxy-5-methylpyrazine (0.4 g, 2.8 mmol), EDCI (0.4 g, 2.6 mmol) and HOAT (0.35 g, 2.7 mmol) were added to a round bottom flask under nitrogen protection 20 mL of dichloromethane was added, cooled to 0°C, DIPEA (1.2 mL, 6.0 mmol) was added slowly, and the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 58-10 (0.16 g, yield: 78%).

MS(ESI, pos.ion) m/z: 844.3 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.09 (s, 1H), 8.38 (s, 1H), 7.51 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.03-6.74 (m ,2H),6.75–6.42(m,2H),5.84(s,1H),5.59(s,1H),5.25(s,1H),4.91(s,1H),4.72(s,4H),4.27( d, J＝44.6Hz, 2H), 4.00(d, J＝6.8Hz, 2H), 2.70(d, J＝43.9Hz, 5H), 2.55–2.00(m, 10H), 1.90(s, 2H), 1.27(s,9H)ppm.

Example 59

synthetic route

Step 1: Synthesis of Compound 59-1

Compound 58-9 (0.25 g, 2.5 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the filter cake was washed with 20 mL of ethyl acetate and the resulting solid was dried in vacuo. The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.4 g, 2.9 mmol), EDCI (0.4 g, 2.6 mmol) and HOAT (0.35 g, 2.7 mmol) were then added to a round bottom flask, 20 mL of dichloromethane was added under nitrogen, then cooled to 0°C and DIPEA (1.2 mL, 6.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 59-1 (0.16 g, yield: 78%).

MS(ESI, pos.ion) m/z: 819.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.87 (d, J=6.6 Hz, 1H), 7.61 (s, 1H), 7.48 (dd, J=8.6, 6.5 Hz, 1H), 7.15 (d, J ＝8.7Hz,1H),6.87(dd,J＝9.0,2.3Hz,1H),6.79(td,J＝8.4,2.3Hz,1H),6.75-6.68(m,2H),6.22(s,1H) ,5.89(s,1H),5.69(s,1H),5.06(s,1H),4.83(s,1H),4.69(s,1H),4.49(s,1H),4.16–4.08(m,1H) ), 4.02(q, J=6.9Hz, 2H), 2.87(s, 1H), 2.75–2.50(m, 3H), 2.51–2.35(m, 4H), 2.26(s, 1H), 2.19–1.89( m, 6H), 1.89–1.64 (m, 3H), 1.30 (dt, J=14.1, 6.7 Hz, 5H) ppm.

Example 60

synthetic route

Step 1: Synthesis of Compound 60-1

Compound 2-13 (0.30 g, 0.39 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo.

The solid obtained above and compound 1-methylpyrazole-3-carboxylic acid (0.05g, 0.39mmol), EDCI (0.1g, 0.67mmol), HOAT (0.1g, 0.6mmol) were added to a round-bottomed flask, nitrogen protection 10 mL of dichloromethane was added at the bottom, then cooled to 0°C, and DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 60-1 (0.160 g, yield: 53%) ppm.

MS(ESI, pos.ion) m/z: 770.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.94 (s, 1H), 7.61 (dd, J=7.7, 1.4 Hz, 1H), 7.34 (d, J=6.5 Hz, 1H), 7.32-7.29 (m ,1H),7.24–7.23(m,1H),7.13(dt,J＝13.7,8.0Hz,5H),6.62(d,J＝2.2Hz,1H),5.95(dd,J＝8.0,4.5Hz, 1H), 5.72 (dd, J=18.2, 8.6Hz, 1H), 5.02–4.97 (m, 1H), 4.68 (ddd, J=9.8, 6.5, 3.2Hz, 1H), 4.53 (t, J=7.2Hz) ,1H),4.36(dd,J＝11.1,2.5Hz,1H),4.18(dd,J＝11.1,5.1Hz,1H),3.87(d,J＝6.5Hz,3H),2.92–2.87(m, 1H), 2.59–2.52(m, 1H), 2.44(dd, J=12.0, 5.9Hz, 2H), 2.27(q, J=8.6Hz, 1H), 2.04(s, 2H), 1.86(dd, J = 8.0, 5.9Hz, 1H), 1.78–1.71 (m, 1H), 1.67 (dd, J=9.3, 5.8Hz, 1H), 1.56–1.42 (m, 6H), 1.34 (dd, J=12.0, 6.0 Hz, 2H), 1.14–1.07 (m, 2H), 0.94–0.86 (m, 2H) ppm.

Example 61

synthetic route

Step 2: Synthesis of Compound 61-1

Compound 2-13 (0.30 g, 0.39 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo.

The solid obtained above, compound 5-methyl-2-thiophenecarboxylic acid (0.06 g, 0.39 mmol), EDCI (0.1 g, 0.67 mmol) and HOAT (0.1 g, 0.6 mmol) were added to a round bottom flask, under nitrogen protection 10 mL of dichloromethane was added, then cooled to 0°C and DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 61-1 (0.12 g, yield: 38%).

MS(ESI, pos.ion) m/z: 786.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J=6.9 Hz, 1H), 7.44 (dd, J=11.4, 3.9 Hz, 2H), 7.30 (d, J=3.6 Hz, 1H), 7.26–7.21(m,1H),7.15(dt,J=14.8,5.5Hz,5H),6.68(dd,J=16.2,4.5Hz,2H),5.97(s,1H),5.71(d,J= 8.6Hz, 1H), 5.04(s, 1H), 4.81(s, 1H), 4.65(s, 1H), 4.47(d, J=10.1Hz, 1H), 4.14(dd, J=13.8, 6.5Hz, 1H), 2.88(s, 1H), 2.61(s, 2H), 2.50(d, J=13.1Hz, 4H), 2.25(dd, J=13.7, 7.9Hz, 1H), 1.87(d, J=6.7 Hz, 4H), 1.48 (dd, J=15.1, 6.5 Hz, 6H), 1.12 (dd, J=21.5, 16.3 Hz, 3H), 0.98–0.82 (m, 3H) ppm.

Example 62

synthetic route

Step 1: Synthesis of Compound 62-2

Compound 62-0 (2.0 g, 14 mmol) and compound 62-1 (2.7 g, 14.8 mmol) were dissolved in 40 mL of DMF, K ₂ CO ₃ (3.41 g, 24.7 mmol) was added, and then the reaction mixture was warmed to reflux, and the reaction overnight. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 100 mL of ethyl acetate, washed with H ₂ O (100 mL x 2), and washed once with 50 mL of saturated brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and the organic solvent was removed under reduced pressure to obtain yellow solid compound 62-2 (4.0 g, yield: 94%), which was directly carried out to the next step without further purification.

MS (ESI, pos.ion) m/z: 304.3 [M+H] ⁺ .

Step 2: Synthesis of Compound 62-3

Compound 62-2 (4.0 g, 13.19 mmol) was dissolved in 100 mL of glacial acetic acid, then reduced iron powder (3.2 g, 57.25 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, and the solid was removed by filtration. The filtrate was poured into 100 ml of 1N HCl solution, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water, and then the obtained solid was dried under vacuum to obtain a white solid compound 62 -3 (2.0 g, yield: 62.8%).

Step 3: Synthesis of Compound 62-4

Compound 62-3 (1.0 g, 4.14 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 62-4 (1.00 g, yield: 93%).

Step 4: Synthesis of Compound 62-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 containing compound 2-7 (1.0 g, 4.3 mmol) was added. mL of anhydrous DMF solution, after which the reaction mixture was warmed to 30°C and stirred for two hours. Then, 5 mL of anhydrous tetrahydrofuran solution containing compound 62-4 (1.0 g, 3.8 mmol) was added to the above reaction solution, and then reacted overnight. The reaction was quenched with 20 mL of water at 0°C, washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1 ) was purified to obtain compound 62-5 as a white solid (1.0 g, yield: 58%).

MS (ESI, pos.ion) m/z: 455.2 [M+H] ⁺ .

Step 5: Synthesis of Compound 62-6

Compound 62-5 (1.0 g, 2.2 mmol), compound 1-9 (0.9 g, 2.2 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0 °C, and then DIPEA (1.05 mL, 6.02 mmol) was added. The reaction mixture was warmed to 30 °C and stirred for 6 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 62-6 (0.86 g, yield: 58.6%).

MS (ESI, pos.ion) m/z: 667.3 [M+H] ⁺ .

Step 6: Synthesis of Compound 62-8

Compound 62-6 (0.80 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate and dried in vacuo.

The solid obtained from the above reaction and compound 2-11 (0.6g, 1.3mmol), EDCI (0.3g, 2mmol), HOAT (0.2g, 1mmol) were added to the round bottom flask, and 20 ml of dichloromethane were added under nitrogen protection, It was then cooled to 0°C and further DIPEA (0.6 mL, 3.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 62-8 (0.92 g, yield: 93.87%).

MS (ESI, pos.ion) m/z: 820.3 [M+H] ⁺ .

Step 7: Synthesis of Compound 62-9

Compound 62-8 (0.5 g, 0.61 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C and stirred for 48 hours . After cooling to room temperature, the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 62-9 (0.3 g, yield: 62.5 %).

MS (ESI, pos.ion) m/z: 792.3 [M+H] ⁺ .

Step 8: Synthesis of Target 62-10

Compound 62-9 (0.3 g, 0.38 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 2-carboxy-5-methylpyrazine (0.06 g, 0.043 mmol), EDCI (0.1 g, 0.65 mmol) and HOAT (0.07 g, 0.54 mmol) were added to a round-bottomed flask under nitrogen. 20 mL of dichloromethane was added under protection, then cooled to 0°C, and then DIPEA (0.2 mL, 1.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 62-10 (0.16 g, yield: 53.3%).

MS(ESI, pos.ion) m/z: 812.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): 10.28 (s, 1H), 9.07 (d, J=23.6 Hz, 1H), 8.40 (d, J=15.0 Hz, 1H), 8.14 (d, J=24.6 Hz, 1H), 7.25–7.20 (m, 1H), 7.19–7.02 (m, 5H), 6.95 (dd, J=8.9, 3.0Hz, 1H), 5.96 (s, 1H), 5.73 (s, 1H), 5.06 (s,1H),4.80(s,1H),4.64(s,2H),4.15(d,J=8.0Hz,1H),3.81–3.63(m,3H),2.90(s,1H),2.74– 2.54 (m, 6H), 2.32 (s, 1H), 2.14–1.90 (m, 2H), 1.74 (s, 8H), 1.21–0.73 (m, 6H) ppm.

Example 63

synthetic route

Step 1: Synthesis of Compound 63-2

Compound 2-10 (0.80 g, 1.5 mmol), compound 63-1 (0.45 g, 1.6 mmol), EDCI (0.3 g, 2 mmol) and HOAT (0.3 g, 1.7 mmol) were added to a round-bottomed flask under nitrogen protection 20 mL of dichloromethane was added at the bottom, then cooled to 0 °C, and DIPEA (1.2 mL, 6.0 mmol) was added slowly. The reaction mixture was then warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed under low temperature, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 63-2 (0.82 g, yield 68.33%).

MS (ESI, pos.ion) m/z: 801.3 [M+H] ⁺ .

Step 2: Synthesis of Compound 63-3

Compound 63-2 (0.5 g, 0.6 mmol) was dissolved in 400 mL of 1,2-dichloroethane, 0.06 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was heated to 65 °C and stirred for 48 hours . After the reaction was completed, it was cooled to room temperature, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 63-3 ( 0.25 g, yield: 51.82%).

MS(ESI, pos.ion) m/z: 773.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.63 (d, J=7.3 Hz, 1H), 7.54 (s, 1H), 7.40 (t, J=7.3 Hz, 1H), 7.23 (d, J=7.1 Hz, 1H), 7.13(d, J=8.9Hz, 5H), 5.97(s, 1H), 5.74(d, J=8.6Hz, 1H), 5.06–4.96(m, 2H), 4.61(t, J ＝6.9Hz,1H),4.50(d,J＝10.8Hz,2H),4.09(d,J＝7.1Hz,1H),3.30(d,J＝5.1Hz,2H),3.24–3.17(m,2H) ), 2.92(s, 1H), 2.64–2.54(m, 3H), 2.26(d, J=8.3Hz, 1H), 2.05(d, J=16.6Hz, 1H), 1.91(d, J=6.1Hz) , 3H), 1.84 (s, 2H), 1.65 (s, 1H), 1.59–1.38 (m, 15H) ppm.

Example 64

synthetic route

Step 1: Synthesis of Compound 64-1

Compound 3-13 (0.30 g, 0.38 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo.

The solid obtained above, compound 2-carboxy-5-methylpyrazine (0.06 g, 0.43 mmol), EDCI (0.1 g, 0.67 mmol) and HOAT (0.1 g, 0.6 mmol) were added to a round bottom flask under nitrogen protection 10 mL of dichloromethane was added at the bottom, then cooled to 0°C, and DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 64-1 (0.14 g, yield: 45%).

MS(ESI, pos.ion) m/z: 812.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.17 (d, J=59.0 Hz, 1H), 8.42 (d, J=12.2 Hz, 1H), 8.34-8.10 (m, 1H), 7.38 (s, 1H) ), 7.28–7.21(m, 2H), 7.13(dt, J=15.2, 6.7Hz, 3H), 6.99(q, J=7.9Hz, 2H), 5.95(s, 1H), 5.70(d, J= 8.7Hz, 1H), 5.09(d, J=9.4Hz, 1H), 4.85(s, 1H), 4.67(s, 1H), 4.44(s, 1H), 4.19(d, J=7.3Hz, 1H) ,3.90(s,3H),2.86(s,1H),2.70–2.48(m,6H),2.27(d,J=8.2Hz,1H),2.04(d,J=8.2Hz,5H),1.90( dd, J=25.6, 18.9 Hz, 3H), 0.89 (dd, J=15.2, 8.2 Hz, 8H) ppm.

Example 65

synthetic route

Step 1: Synthesis of Compound 65-2

Compound 65-0 (2.0 g, 14 mmol) and compound 65-1 (2.7 g, 14.8 mmol) were dissolved in 40 mL of DMF, and K ₂ CO ₃ (3.41 g, 24.7 mmol) was added thereto, after which the reaction mixture was warmed to Reflux and react overnight. After the reaction was completed, it was cooled to room temperature, and 100 mL of ethyl acetate was added, followed by washing with H ₂ O (100 mL x 2) and once with 50 mL of saturated brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and the organic solvent was removed under reduced pressure to obtain yellow solid compound 65-2 (4.0 g, yield: 94%), which was directly carried out to the next step without further purification.

MS (ESI, pos.ion) m/z: 304.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 65-3

Compound 65-2 (4.0 g, 13.19 mmol) was dissolved in 100 mL of glacial acetic acid, and then reduced iron powder (3.2 g, 57.25 mmol) was added. The reaction mixture was warmed to 115°C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered to remove the solid, 100 ml of 1N HCl solution was added dropwise to the filtrate, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 65-3 (2.0 g, yield : 62.9%).

Step 3: Synthesis of Compound 65-4

Compound 65-3 (1.0 g, 4.14 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.65 mL, 7.0 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol). The temperature of the reaction mixture was raised to 110°C, and the reaction was carried out for 6 hours. After the reaction was completed, it was cooled to 0°C, the organic solvent was removed under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a white solid compound 65-4 ( 1.00 g, yield: 93%).

Step 4: Synthesis of Compound 65-5

Sodium hydride (0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, cooled to 0 °C under nitrogen protection, and then 10 mL of anhydrous DMF solution containing compound 2-7 (1.0 g, 4.3 mmol) was added, and then the reaction was carried out. The mixture was warmed to 30°C and stirred for two hours. A solution of compound 65-4 (1.0 g, 3.8 mmol) in 5 mL of anhydrous tetrahydrofuran was added to the above reaction solution, and then reacted overnight. The reaction was quenched with 20 mL of water at 0°C, then washed once with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, then extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed from the filtrate under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2: 1) Purification to obtain white solid compound 65-5 (1.0 g, yield: 58%).

MS (ESI, pos.ion) m/z: 455.2 [M+H] ⁺ .

Step 5: Synthesis of Compound 65-6

Compound 65-5 (1.0 g, 2.2 mmol), compound 1-9 (0.9 g, 2.2 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen 30 mL of dichloromethane was added under protection, then cooled to 0°C, then DIPEA (1.05 mL, 6.02 mmol) was added, and the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was complete, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phase was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure to remove the organic solvent, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2 : 1) was purified to obtain compound 65-6 as a white solid (0.86 g, yield: 58.6%).

MS (ESI, pos.ion) m/z: 667.3 [M+H] ⁺ .

Step 6: Synthesis of Compound 65-8

Compound 65-6 (0.80 g, 1.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After filtration, the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 2-11 (0.6g, 1.3mmol), EDCI (0.3g, 2mmol), HOAT (0.2g, 1mmol) were added to the round-bottom flask, and 20 ml of dichloromethane were added under nitrogen protection, It was then cooled to 0°C and further DIPEA (0.6 mL, 3.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, and then extracted with ethyl acetate (10 mL x 3), the organic phases were combined, and the organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in size. The organic solvent was removed under pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 65-8 (0.92 g, yield: 93.9%) .

MS (ESI, pos.ion) m/z: 820.3 [M+H] ⁺ .

Step 7: Synthesis of Compound 65-9

Compound 65-8 (0.5 g, 0.61 mmol) was dissolved in 400 ml of 1,2-dichloroethane, 0.07 g of Grubbs second-generation catalyst was added under nitrogen protection, and then the reaction mixture was warmed to 65 °C, and at this temperature under stirring for 48 hours. After cooling to room temperature, the organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 65-9 (0.3 g, yield: 62.5 %).

Step 8: Synthesis of Compounds 65-10

Compound 65-9 (0.3 g, 0.38 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 2 mL of 30% ethyl acetate solution of hydrochloric acid was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 2-carboxy-5-methylpyrazine (0.06 g, 0.043 mmol), EDCI (0.1 g, 0.65 mmol) and HOAT (0.07 g, 0.54 mmol) were added to a round-bottomed flask under nitrogen. 20 mL of dichloromethane was added under protection, then cooled to 0°C, and then DIPEA (0.2 mL, 1.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed under low temperature, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 65-10 (0.10 g, yield: 32.46%).

MS(ESI, pos.ion) m/z: 812.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.38 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 8.19 (d, J=7.2 Hz, 1H), 7.64 (s, 1H) ),7.47(d,J=8.7Hz,1H),7.23(d,J=7.3Hz,1H),7.12(d,J=2.3Hz,2H),6.67(d,J=2.4Hz,1H), 6.61 (dd, J=8.7, 2.4Hz, 1H), 5.94 (s, 1H), 5.74 (dd, J=18.2, 8.7Hz, 1H), 5.04–4.98 (m, 1H), 4.83–4.76 (m, 1H), 4.62(t, J＝7.6Hz, 1H), 4.47(d, J＝11.4Hz, 1H), 4.15(dd, J＝11.3, 4.4Hz, 1H), 3.77(s, 3H), 3.69– 3.58(m,1H),2.91(ddd,J=13.0,8.0,4.9Hz,1H),2.64-2.48(m,7H),2.37-2.23(m,2H),1.80-1.74(m,1H), 1.63–1.59 (m, 1H), 1.53–1.45 (m, 5H), 1.14–1.10 (m, 2H), 0.96–0.82 (m, 4H) ppm.

Example 66

synthetic route

Step 1: Synthesis of Compound 66-1

Compound 3-13 (0.30 g, 0.38 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo.

The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.05g, 0.39mmol), EDCI (0.1g, 0.67mmol), HOAT (0.1g, 0.6mmol) were added to a round bottom flask, nitrogen 10 mL of dichloromethane was added under protection, then cooled to 0°C, and then DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 66-1 (0.12 g, yield 39.5%).

MS(ESI, pos.ion) m/z: 801.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.35 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.55 (s, 1H), 7.24-7.06 (m, 3H), 7.02-6.95 (m,3H),6.13(s,1H),5.96(d,J=3.1Hz,1H),5.76(dd,J=17.9,8.7Hz,1H),5.04–4.98(m,1H),4.85( t, J=7.6Hz, 1H), 4.69–4.59 (m, 2H), 4.12 (dd, J=11.5, 4.0Hz, 1H), 3.91 (s, 3H), 3.77–3.61 (m, 2H), 3.50 (q, J=7.0Hz, 3H), 2.95–2.89 (m, 1H), 2.67 (dd, J=7.7, 3.2Hz, 3H), 2.44–2.27 (m, 3H), 1.97–1.83 (m, 3H) ), 1.52–1.48 (m, 3H), 0.99–0.83 (m, 6H) ppm.

Example 67

synthetic route

Step 1: Synthesis of Compound 67-1

Compound 65-9 (0.3 g, 0.38 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo.

The solid obtained above, 5-methylisoxazole-3-carboxylic acid (0.05 g, 0.39 mmol), EDCI (0.1 g, 0.67 mmol), HOAT (0.1 g, 0.6 mmol) were added to a round-bottomed flask under nitrogen protection 10 mL of dichloromethane was added at the bottom, then cooled to 0°C, and DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 67-1 (0.15 g, yield: 49.3%).

MS(ESI, pos.ion) m/z: 801.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.44 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.24(d,J＝7.4Hz,1H),7.14(dt,J＝13.7,4.3Hz,3H),6.68(d,J＝2.4Hz,1H),6.57(dd,J＝8.7,2.4Hz,1H) ), 6.17(s, 1H), 5.93(d, J=2.9Hz, 1H), 5.74(dd, J=18.0, 8.8Hz, 1H), 5.02–4.96(m, 1H), 4.84(dd, J= 13.2, 5.3Hz, 1H), 4.67(t, J=7.8Hz, 1H), 4.59(d, J=11.5Hz, 1H), 4.12(dd, J=11.4, 4.2Hz, 1H), 3.79(s, 3H), 2.92(ddd, J＝13.0, 8.1, 4.9Hz, 1H), 2.65(d, J＝7.7Hz, 3H), 2.39(s, 3H), 2.32(d, J＝8.6Hz, 1H), 2.11 (d, J=4.8Hz, 1H), 1.85 (ddd, J=13.9, 8.6, 5.1Hz, 2H), 1.54–1.38 (m, 8H), 1.00–0.80 (m, 4H) ppm.

Example 68

synthetic route

Step 1: Synthesis of Compound 68-1

Compound 62-9 (0.3 g, 0.38 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo. The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.05 g, 0.39 mmol), EDCI (0.1 g, 0.67 mmol), HOAT (0.1 g, 0.6 mmol) were added to a round bottom flask, nitrogen 10 mL of dichloromethane was added under protection, then cooled to 0°C, and then DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 68-1 (0.16 g, yield: 52.6%).

MS(ESI, pos.ion) m/z: 801.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.38 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.69 (s, 1H), 7.19-7.08 (m, 5H), 6.94-6.88 (m, 2H), 6.13 (s, 1H), 5.98–5.69 (m, 3H), 5.46–5.29 (m, 1H), 5.05–4.89 (m, 2H), 4.83 (t, J=8.0Hz, 1H) ),4.68(dd,J＝19.4,10.7Hz,2H),4.11(dd,J＝11.5,4.0Hz,1H),3.78(dd,J＝12.7,7.8Hz,1H),3.50(q,J＝ 7.0Hz, 6H), 2.96–2.91 (m, 1H), 2.72–2.63 (m, 3H), 2.49 (d, J=8.3Hz, 1H), 2.43–2.29 (m, 5H), 2.04 (dd, J =19.0, 11.1 Hz, 3H), 0.90 (m, 3H) ppm.

Example 69

synthetic route

Step 1: Synthesis of Compound 69-1

Compound 2-13 (0.30 g, 0.39 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo. The solid obtained above, compound 6-methylpyridine-3-carboxylic acid (0.06g, 0.43mmol), EDCI (0.1g, 0.67mmol), HOAT (0.1g, 0.6mmol) were added to a round bottom flask, under nitrogen protection 10 mL of dichloromethane was added, then cooled to 0°C and DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 69-1 (0.16 g, yield: 53%).

MS(ESI, pos.ion) m/z: 781.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.99 (d, J=1.3 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J=6.8 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H), 7.62 (dd, J=7.7, 1.2Hz, 1H), 7.48–7.42 (m, 1H), 7.25 (dd, J=7.5, 1.6Hz, 1H), 7.18 (d, J=7.9Hz) ,1H),7.17–7.13(m,3H),7.13–7.08(m,2H),5.97(d,J=34.0Hz,1H),5.67(dd,J=18.1,8.5Hz,1H),4.94( dd, J=18.9, 10.0Hz, 1H), 4.79 (d, J=11.5Hz, 1H), 4.75–4.69 (m, 1H), 4.65 (q, J=7.7Hz, 1H), 4.16–4.07 (m ,1H),2.94–2.85(m,1H),2.64(dd,J=13.9,8.0Hz,1H),2.60–2.47(m,5H),2.17(q,J=8.5Hz,1H),2.05( s, 5H), 1.88–1.80 (m, 1H), 1.78 (dd, J=7.9, 6.2Hz, 1H), 1.65–1.59 (m, 1H), 1.52–1.42 (m, 4H), 1.37–1.32 ( m, 2H), 1.13-0.88 (m, 2H) ppm.

Example 70

synthetic route

Step 1: Synthesis of Compound 70-1

Compound 2-13 (0.30 g, 0.39 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 5 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature until no more The reaction ends when the gas evolves. After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with 10 mL of ethyl acetate, and the obtained solid was dried in vacuo. The solid obtained above, compound 5-methyl-2-carboxylic acid pyridine (0.06 g, 0.43 mmol), EDCI (0.1 g, 0.67 mmol) and HOAT (0.1 g, 0.6 mmol) were added to a round bottom flask, under nitrogen protection 10 mL of dichloromethane was added, then cooled to 0 °C and DIPEA (0.2 mL, 1.0 mmol) was added slowly. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, 10 mL of water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed under reduced pressure The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 70-1 (0.13 g, yield: 43.6%).

MS(ESI, pos.ion) m/z: 781.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.47-8.36 (m, 2H), 7.92-7.78 (m, 2H), 7.57 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.6 Hz ,1H),7.33(t,J＝7.4Hz,1H),7.23(d,J＝7.0Hz,1H),7.12(ddd,J＝18.3,16.7,8.2Hz,5H),5.91(s,1H) ,5.71(dd,J＝17.4,8.3Hz,1H),5.04(t,J＝9.3Hz,1H),4.76(s,1H),4.57(t,J＝6.8Hz,1H),4.39(t, J=15.7Hz, 1H), 4.18 (dd, J=10.9, 4.6Hz, 1H), 2.89 (s, 1H), 2.54 (s, 1H), 2.43–2.25 (m, 6H), 2.10–1.86 (m ,4H),1.79(s,1H),1.68–1.63(m,1H),1.45(dd,J=23.2,9.7Hz,5H),1.07(ddd,J=40.4,22.2,5.9Hz,3H), 0.89 (d, J=6.8 Hz, 2H) ppm.

Example 71

synthetic route

Step 1: Synthesis of Compound 71-1

Compound 71-0 (944 mg, 3.1 mmol) was added to 10 mL of toluene, and under nitrogen protection and stirring, POCl ₃ (939 mg, 6.1 mmol) and N,N-dimethylaniline (185 mg, 1.5 mmol) were slowly added. After the addition, the temperature of the reaction solution was raised to 110°C for 5 hours. After the reaction was completed, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 71-1 (0.8 g, yield 80%) as a pale yellow solid.

Step 2: Synthesis of Compound 71-2

N-Boc-4-(R)-Hydroxyproline (1.5 g, 6.5 mmol) was dissolved in 50 mL of DMF, cooled to 0 °C under nitrogen protection, and NaH (30% dispersed in mineral oil, 520 mg, 13 mmol) was added. ), and then warmed to room temperature and stirred for 2 hours.

Compound 71-1 (2.1 g, 6.5 mmol) was dissolved in 10 mL of DMF, the resulting solution was added to the above reaction solution, and stirring was continued for 4 hours. After the reaction, pour the reaction solution into 50 mL of water, adjust the pH value to about 2-3 with 1N HCl aqueous solution, then extract with ethyl acetate (20 mL×3), combine the organic phases, and use saturated sodium chloride for the combined organic phase. The solution was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain Light yellow solid compound 71-2 (3.0 g, yield 90%).

MS(ESI,neg.ion)m/z:518.9[MH] ^– .

Step 3: Synthesis of Compound 71-3

Compound 71-2 (50 mg, 0.1 mmol), compound 1-9 (42 mg, 0.1 mmol), EDCI (24 mg, 0.12 mmol), HOAT (17 mg, 0.12 mmol) and 15 mL of dichloromethane were sequentially added to a round-bottomed flask , at 0 °C, and then DIPEA (48 mg, 0.37 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction is completed, adjust the pH value to about 2 with 1N hydrochloric acid solution, then extract the aqueous phase with dichloromethane (10 mL×2), combine the organic phases, wash the combined organic phases with saturated sodium chloride solution, and then use anhydrous It was dried over sodium sulfate and filtered, the obtained filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 71-3 as a pale yellow solid (50 mg, 70% yield).

MS (ESI, pos.ion) m/z: 734.9 [M+H] ⁺ .

Step 4: Synthesis of Compound 71-5

Compound 71-3 (600 mg, 0.8 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue (300 mg, 0.45 mmol) was dissolved in CH ₂ Cl ₂ (50 mL), and compound 2-11 (223 mg, 0.49 mmol), EDCI (103 mg, 0.54 mmol) and HOAT (73 mg, 0.54 mmol) were added thereto. ), under nitrogen at 0°C, further DIPEA (177 mg, 1.3 mmol) was added and the resulting reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 71-5 (0.34 g, collected in two steps) as a light yellow solid. rate 64%).

Step 5:: Synthesis of Compounds 71-6

Compound 71-5 (230 mg, 0.28 mmol) was dissolved in 300 mL of 1,2-dichloroethane, 30 mg of Jan's 1B catalyst was added under nitrogen protection, the reaction mixture was heated to 75° C. and reacted for 48 hours. After the reaction was completed, it was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 71-6 (160 mg, yield 73%) as a white solid.

MS(ESI, pos.ion) m/z: 859.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.44 (d, J=93.7 Hz, 1H), 7.67-7.45 (m, 1H), 7.35 (d, J=39.0 Hz, 1H), 7.23 (d, J =13.1Hz,2H),7.00(d,J=8.4Hz,1H),6.94-6.81(m,2H),5.90(d,J=34.1Hz,1H),5.72(dd,J=17.6,8.7Hz ,1H),5.25(d,J=7.1Hz,1H),4.99(t,J=9.3Hz,1H),4.75–4.51(m,2H),4.32(s,1H),4.03(t,J= 24.9Hz, 1H), 2.92 (s, 1H), 2.75–2.45 (m, 3H), 2.33 (d, J=8.3Hz, 1H), 1.97–1.79 (m, 4H), 1.45 (d, J=10.8 Hz, 5H), 1.29 (m, 9H), 1.16–0.78 (m, 6H) ppm.

HPLC purity: 97.49%.

Example 72

synthetic route

Step 1: Synthesis of Compound 72-2

Compound 72-1 (100 mg, 0.27 mmol) was dissolved in 100 mL of glacial acetic acid, and iron powder (74 mg, 1.3 mmol) was added thereto, and the reaction mixture was warmed to 110° C. and stirred for 8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered again, the obtained filtrate was poured into 200 mL of water, a solid was precipitated, filtered, and the filter cake was washed with water, and the obtained solid was placed in a vacuum drying oven to dry to obtain a yellow solid compound 72-2 (70 mg , the yield is 84%).

Step 2: Synthesis of Compound 72-3

Compound 72-2 (944 mg, 3.0 mmol) was added to 10 mL of toluene, and under nitrogen protection, POCl ₃ (927 mg, 6.0 mmol) and N,N-dimethylaniline (183 mg, 1.51 mmol) were slowly added, and the addition was complete. After that, the temperature of the reaction mixture was raised to 110°C for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 72-3 as a pale yellow solid (0.8 g, yield 80%).

Step 3: Synthesis of Compound 72-4

N-Boc-4-(R)-Hydroxyproline (573 mg, 2.48 mmol) was dissolved in 50 mL of DMF, and NaH (60% in mineral oil, dispersed in mineral oil, 60% dispersed in mineral oil) was added in portions under nitrogen protection at 0°C. 247 mg, 6.2 mmol). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes.

Compound 72-3 (820 mg, 2.48 mmol) was dissolved in a small amount of DMF and added to the above reaction mixture, and stirring was continued at room temperature for 2 hours. After the reaction, the reaction was quenched with 50 mL of water, the pH value of the aqueous phase was adjusted to about 2-3 with 1N HCl aqueous solution, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the combined organic phases were washed with saturated chlorine Washed with sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain Light yellow solid compound 72-4 (1 g, yield 77%).

MS (ESI, pos.ion) m/z: 526.3 [M+H] ⁺ .

Step 4: Synthesis of Compound 72-5

Compound 72-4 (720 mg, 1.4 mmol), compound 1-9 (661 mg, 1.6 mmol), EDCI (317 mg, 1.6 mmol) and HOAT (225 mg, 1.6 mmol) were added to 100 mL of CH ₂ Cl ₂ and then cooled to At 0°C, additional DIPEA (546 mg, 4.1 mmol) was added, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 72-5 (0.8 g , the yield is 80%).

Step 5: Synthesis of Compound 72-7

Compound 72-5 (810 mg, 1.1 mmol) was dissolved in 5N HCl in 50 mL of ethyl acetate and stirred at room temperature for 3 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure. The resulting residue (300 mg, 0.4 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , then compound 2-11 (221 mg, 0.5 mmol), EDCI (102 mg, 0.5 mmol) and HOAT (72 mg, 0.5 mmol) were added under nitrogen protection DIPEA (176 mg, 1.3 mmol) was added under ice-bath condition, then warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain a pale yellow solid compound 72-7 (0.3 g , the yield is 80%). MS (ESI, pos.ion) m/z: 791 [M+H-100] ⁺ .

Step 6: Synthesis of Compound 72-8

Compound 72-7 (130 mg, 0.18 mmol) was dissolved in 300 mL of 1,2-dichloroethane, Jan's 1B catalyst (13 mg, 0.017 mmol) was added under nitrogen protection, and the reaction mixture was heated to 75 °C for 36 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 72-8 (155 mg, yield 65%) as a white solid.

MS(ESI,neg.ion)m/z:861[MH] ^- ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.41 (d, J=116.1 Hz, 1H), 7.88 (t, J=9.6 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J=8.0 Hz,1H),7.63–7.53(m,1H),7.35(s,1H),7.29(d,J=4.2Hz,1H),7.04(d,J=18.9Hz,1H),6.97(d,J =8.1Hz,1H),6.87(s,1H),5.93(s,1H),5.74(dd,J=17.5,8.7Hz,1H),5.16(d,J=7.3Hz,1H),5.01(t , J=9.3Hz, 1H), 4.34(t, J=7.4Hz, 1H), 4.06(t, J=27.1Hz, 1H), 2.93(s, 1H), 2.63(d, J=41.3Hz, 3H) ), 2.30 (dd, J=31.5, 23.5Hz, 1H), 1.99–1.78 (m, 3H), 1.73 (s, 2H), 1.57 (d, J=33.1Hz, 1H), 1.53–1.44 (m, 4H), 1.37–1.26 (m, 11H), 1.13 (ddd, J=20.7, 12.6, 6.4Hz, 2H), 0.98–0.80 (m, 3H) ppm.

HPLC purity: 94.71%.

Example 73

synthetic route

Step 1: Synthesis of Intermediate 73-1

Compound _73-0 (1.0 g, 3.0 mmol) was added to 20 mL of toluene, POCl (927 mg, 6.0 mmol) and N,N-dimethylaniline (183 mg, 1.51 mmol) were slowly added under nitrogen protection and stirring, and the addition was complete. After that, the temperature of the reaction solution was raised to 110° C. to react for 3 hours. After the completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 73-1 (0.8 g, yield 80%) as a pale yellow solid.

Step 2: Synthesis of Compound 73-2

The compound N-Boc-4-(R)-hydroxyproline (573 mg, 2.48 mmol) was dissolved in 50 mL of DMF, cooled to 0 °C under nitrogen protection, and then NaH (60% dispersed in mineral oil, 247 mg, 6.2 mmol), after the addition was complete, the reaction solution was brought to room temperature and stirred for 30 minutes.

Compound 73-1 (875 mg, 2.48 mmol) was dissolved in 10 mL of anhydrous DMF solution, added to the above reaction solution, and the resulting mixture was further stirred for 2 hours. After the reaction, the reaction solution was poured into 50 mL of water, and the pH value was adjusted to 2-3 with 1N HCl, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution. It was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 73-2 (1 g, yield 77%).

MS (ESI, pos.ion) m/z: 549.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 73-3

Compound 73-2 (767 mg, 1.4 mmol), compound 1-9 (661 mg, 1.6 mmol), EDCI (317 mg, 1.6 mmol) and HOAT (225 mg, 1.6 mmol) were added to 100 mL of CH ₂ Cl ₂ under ice bath DIPEA (546 mg, 4.1 mmol) was added, and after the addition was completed, the mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 73-3 (0.8 g, yield 80%).

Step 4: Synthesis of Compound 73-5

Compound 73-3 (891 mg, 1.1 mmol) was dissolved in 5N HCl in 50 mL of ethyl acetate, and stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue (300 mg, 0.4 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , compound 2-11 (221 mg, 0.5 mmol), EDCI (102 mg, 0.5 mmol) and HOAT (72 mg, 0.5 mmol) were added, and the resulting mixture was DIPEA (176 mg, 1.3 mmol) was added under an ice bath, followed by stirring at room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain a pale yellow solid compound 73-5 (0.3 g, collected rate 80%).

MS (ESI, pos.ion) m/z: 914.4 [M+H] ⁺ .

Step 5: Synthesis of Compound 73-6

Compound 73-5 (165 mg, 0.18 mmol) was dissolved in 1,2-dichloroethane (300 mL), and Jan's 1B catalyst (13 mg, 0.017 mmol) was added under nitrogen protection, and then the temperature was raised to 75°C for 36 hours. . After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 73-6 (103 mg, yield 65%) as a white solid.

MS(ESI, pos.ion) m/z: 886[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.48 (d, J=116.1 Hz, 1H), 7.56 (d, J=33.0 Hz, 1H), 7.40-7.30 (m, 4H), 7.26 (d, J =7.5Hz,1H),7.09–6.96(m,2H),6.92(d,J=8.2Hz,1H),6.86(s,1H),5.95(s,1H),5.74(dd,J=17.2, 8.5Hz, 1H), 5.34 (d, J=34.4Hz, 1H), 5.01 (t, J=9.3Hz, 1H), 4.63 (dd, J=69.3, 29.5Hz, 2H), 4.37 (t, J= 7.4Hz, 1H), 4.09(dd, J=45.1, 13.5Hz, 1H), 3.84(s, 3H), 2.93(s, 1H), 2.63(dd, J=23.8, 17.0Hz, 3H), 2.30( ddd, J=26.0, 16.4, 6.7Hz, 2H), 1.97–1.82 (m, 4H), 1.60 (s, 1H), 1.46 (d, J=14.7Hz, 5H), 1.33 (d, J=22.5Hz) , 9H), 1.19–1.09 (m, 2H), 0.98–0.84 (m, 3H) ppm.

HPLC purification: 92.90%.

Example 74

synthetic route

Step 1: Synthesis of Compound 74-1

Compound _74-0 (0.86 g, 3.0 mmol) was added to 20 mL of toluene, and POCl (927 mg, 6.0 mmol) and N,N-dimethylaniline (183 mg, 1.51 mmol) were slowly added under stirring. After the addition, The temperature of the reaction solution was raised to 110°C for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 74-1 (734 mg, yield 80%) as a pale yellow solid.

Step 2: Synthesis of Compound 74-2

Compound N-Boc-4-(R)-hydroxyproline (759 mg, 2.48 mmol) was dissolved in DMF (50 mL), the reaction solution was protected with nitrogen, and cooled to 0 °C, then NaH (60%) was added in portions Disperse in mineral oil, 247 mg, 6.2 mmol), after addition, the reaction solution was warmed to room temperature and stirred for 30 minutes.

Compound 74-1 (875 mg, 2.48 mmol) was dissolved in 10 mL of anhydrous DMF, and then added to the above reaction solution, and the resulting mixture was further stirred for 2 hours. After the reaction, the reaction solution was poured into 50 mL of water, and the pH value was adjusted to 2-3 with 1N HCl solution, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, and anhydrous It was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 74-2 (0.957 g) after purification. , the yield is 77%).

MS (ESI, pos.ion) m/z: 501.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 74-3

Compound 74-2 (701 mg, 1.4 mmol), compound 1-9 (661 mg, 1.6 mmol), EDCI (317 mg, 1.6 mmol) and HOAT (225 mg, 1.6 mmol) were added to 100 mL of CH ₂ Cl ₂ under ice bath DIPEA (546 mg, 4.1 mmol) was added, and after the addition was completed, the mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 74-3 (0.79 g , the yield is 80%).

Step 4: Synthesis of Compound 74-5

Compound 74-3 (2.0 g, 2.8 mmol) was dissolved in 5N HCl in 50 mL of ethyl acetate, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained crude product (200 mg, 0.3 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , and compound 2-11 (157 mg, 0.33 mmol), EDCI (70 mg, 0.37 mmol) and HOAT (50 mg, 0.37 mmol) were added thereto, and then DIPEA (122 mg, 0.9 mmol) was added under an ice bath and the resulting mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain compound 74-5 (0.2 g, yield) as a light yellow solid. rate 74%).

Step 5: Synthesis of Compound 74-6

Compound 74-5 (200 mg, 0.22 mmol) was dissolved in 300 mL of 1,2-dichloroethane, Jan's 1B catalyst (17 mg, 0.02 mmol) was added under nitrogen protection, and the reaction solution was heated to 75°C for 36 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 74-6 (100 mg, yield 50%) as a white solid.

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.44 (s, 1H), 7.90 (s, 1H), 7.72-7.53 (m, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.84 (dd , J＝19.6, 8.6Hz, 2H), 6.72–6.65(m, 2H), 5.94(s, 1H), 5.71(dd, J＝17.6, 8.5Hz, 1H), 5.23(d, J＝5.5Hz, 1H), 4.95(t, J＝9.3Hz, 1H), 4.83(d, J＝5.3Hz, 1H), 4.61(t, J＝7.5Hz, 1H), 4.55–4.46(m, 3H), 4.06( dd,J＝11.0,3.6Hz,1H),3.85(dd,J＝13.0,6.5Hz,1H),2.89(d,J＝4.3Hz,1H),2.61–2.49(m,3H),2.28(dd , J＝16.7, 8.2Hz, 1H), 1.99(s, 2H), 1.92-1.87(m, 2H), 1.85-1.78(m, 2H), 1.75(d, J＝11.4Hz, 1H), 1.61( s, 4H), 1.55–1.50 (m, 2H), 1.43 (dd, J=14.9, 5.7Hz, 6H), 1.34 (d, J=5.9Hz, 6H), 0.90 (ddd, J=16.0, 14.3, 7.0Hz, 4H)ppm. HPLC purity: 95.75%.

Example 75

synthetic route

Step 1: Synthesis of Compound 75-1

Compound 75-0 (0.86g, 3.0mmol) was added to 20mL of toluene, POCl ( _927mg , 6.0mmol) and N,N-dimethylaniline (183mg, 1.51mmol) were slowly added under nitrogen protection, after the addition The temperature was raised to 110°C and the reaction was refluxed for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 75-1 (734 mg, yield 80%) as a pale yellow solid after purification.

Step 2: Synthesis of Compound 75-2

Compound N-Boc-4-(R)-hydroxyproline (759 mg, 2.48 mmol) was dissolved in 50 mL of DMF, and the resulting mixture was cooled to 0 °C under nitrogen protection, and NaH (60% dispersed in In mineral oil, 247 mg, 6.2 mmol), after the addition was completed, it was warmed to room temperature and stirred for 30 minutes.

Compound 75-1 (875 mg, 2.48 mmol) was dissolved in 10 mL of anhydrous DMF, the resulting mixture was added to the above solution, and stirring was continued for 2 hours. After the reaction, the reaction solution was poured into 50 mL of water, the pH of the resulting mixture was adjusted to 2-3 with 1N HCl solution, then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution Washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 75- 2 (0.957 g, 77% yield).

MS (ESI, pos.ion) m/z: 501.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 75-3

Compound 75-2 (701 mg, 1.4 mmol), compound 1-9 (661 mg, 1.6 mmol), EDCI (317 mg, 1.6 mmol) and HOAT (225 mg, 1.6 mmol) were added to 100 mL of CH ₂ Cl ₂ , followed by placing on ice DIPEA (546 mg, 4.1 mmol) was added under bath. The reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was removed from the reaction solution under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 75-3 (0.79 g, yield 80%).

Step 4: Synthesis of Compound 75-6

Compound 75-3 (2.0 g, 2.8 mmol) was dissolved in 5N HCl in 50 mL of ethyl acetate, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained crude product (200 mg, 0.3 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ and compound 75-5 (147 mg, 0.3 mmol), EDCI (70 mg, 0.37 mmol) and HOAT (50 mg, 0.37 mmol) were added thereto, DIPEA (122 mg, 0.9 mmol) was finally added under an ice bath and the reaction was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain a pale yellow solid compound 75-6 (0.15 g , the yield is 55%).

Step 5: Synthesis of Compound 75-7

Compound 75-6 (200 mg, 0.22 mmol) was dissolved in 300 mL of 1,2-dichloroethane, Jan's 1B catalyst (17 mg, 0.02 mmol) was added under nitrogen protection, and the reaction solution was heated to 75°C for 36 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by preparative HPLC to obtain a white solid compound 75-7 (100 mg, yield 50%).

MS(ESI, pos.ion) m/z: 863.0[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.29(s, 1H), 7.60(s, 1H), 7.11(d, J=7.5Hz, 1H), 6.87(s, 2H), 6.69(d, J ＝14.9Hz, 2H), 5.92(s, 1H), 5.74(s, 1H), 5.37(s, 1H), 4.95(d, J＝46.4Hz, 2H), 4.51(dd, J＝59.7, 46.9Hz) ,4H),4.30–3.92(m,3H),3.48–3.13(m,2H),2.92(s,1H),2.61(s,2H),2.28(s,1H),2.06(d,J=24.6 Hz, 1H), 1.88 (s, 4H), 1.31 (d, J=38.7 Hz, 22H), 0.92 (d, J=30.1 Hz, 4H) ppm.

HPLC purity: 94.93%.

Example 76

synthetic route

Step 1: Synthesis of Compound 76-2

Compound 76-0 (50 mg, 0.29 mmol) and compound 76-1 (50 mg, 0.35 mmol) were dissolved in 20 mL of DMF, then K ₂ CO ₃ (60 mg, 0.44 mmol) was added, and the reaction solution was heated to 110° C. and reacted overnight. After the reaction was completed, 1 mL of water was added to quench the reaction, and then extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated by evaporation under reduced pressure. The compound 76-2 was obtained as an orange oily liquid, and the next reaction was carried out without further purification.

MS (ESI, pos.ion) m/z=292.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 76-3:

Compound 76-2 (1 g, 3.4 mmol) obtained in the previous reaction was dissolved in 50 mL of glacial acetic acid, iron powder (0.96 g, 17.2 mmol) was added thereto, and the temperature was raised to 110° C. for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then filtered. The obtained filtrate was concentrated and poured into 1N 100 mL hydrochloric acid solution. There was solid precipitation, which was filtered, and the filter cake was washed with water. The obtained solid was dried in a vacuum oven to obtain a yellow solid compound. 76-3 (822mg, 61% yield in two steps)

Step 3: Synthesis of Compound 76-4

Compound 76-3 (50 mg, 0.22 mmol) was added to 20 mL of toluene, and under nitrogen protection, POCl ₃ (100 mg, 0.66 mmol) and N,N-dimethylaniline (13 mg, 0.11 mmol) were slowly added thereto, After the addition, the temperature of the reaction solution was raised to 110°C for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 76-4 (35 mg, yield 64%) as a pale yellow solid.

MS(ESI, pos.ion) m/z: 248.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 76-5

Compound N-Boc-4-(R)-hydroxyproline (60 mg, 0.24 mmol) was dissolved in 10 mL of DMF, and the resulting mixture was cooled to 0 °C under nitrogen protection, and then NaH (60% dispersed in In mineral oil, 25 mg, 0.6 mmol), after the addition, the reaction solution was warmed to room temperature and stirred for 2 hours.

Compound 76-4 (60 mg, 0.24 mmol) was dissolved in 10 mL of anhydrous DMF, added to the above reaction solution, and stirring was continued for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, the pH of the resulting mixture was adjusted to 2-3 with 1N HCl solution, and then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution Washed, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a pale yellow solid compound 76-5 (85 mg, 80% yield).

MS (ESI, pos.ion) m/z: 443.1 [M+H] ⁺ .

Step 5: Synthesis of Compound 76-6

Compound 76-5 (50 mg, 0.11 mmol), compound 1-9 (45 mg, 0.11 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to 15 mL of CH ₂ Cl ₂ under ice bath DIPEA (48 mg, 0.37 mmol) was added, and after the addition was completed, the mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the pH value was adjusted to about 2 with 1N hydrochloric acid, then extracted with dichloromethane (10 mL×2), the organic phases were combined, the extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced in pressure. The organic solvent was spin-dried, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 76-6 as a pale yellow solid (65 mg, yield 90%).

MS (ESI, pos.ion) m/z: 655.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 76-8

Compound 76-6 (1.15 g, 1.8 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in 50 mL of CH ₂ Cl ₂ , then compound 2-11 (488 mg, 1.8 mmol), EDCI (546 mg, 2.85 mmol) and HOAT (388 mg, 2.85 mmol) were added to the obtained mixture, and the mixture was heated in an ice bath. DIPEA (924 mg, 7.15 mmol) was added and the reaction was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 76-8 (400 mg, two steps) as a light yellow solid yield 40%).

MS (ESI, pos.ion) m/z: 808.3 [M+H] ⁺ .

Step 7: Synthesis of Compound 76-9

Compound 76-8 (230 mg, 0.28 mmol) was dissolved in 300 mL of 1,2-dichloroethane, and Jan's 1B catalyst (30 mg) was added thereto under nitrogen protection, and the reaction solution was heated to 75° C. for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 76-9 (160 mg, yield 73%) as a white solid.

MS (ESI, pos.ion) m/z: 780.2 [M+H] ⁺ .

Step 8: Synthesis of Compounds 76-10

Compound 76-9 (339 mg, 0.38 mmol) was dissolved in 5N HCl in EA solution (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a white solid compound 76-10 (0.29 g, yield 99%).

Step 9: Synthesis of Compounds 76-11

Compound 76-10 (150 mg, 0.21 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , to which was added compound 5-methylpyrazine-2-carboxylic acid (32 mg, 0.23 mmol), EDCI (48 mg, 0.25 mmol) and HOAT (34 mg, 0.25 mmol), then DIPEA (82 mg, 0.63 mmol) was added under an ice bath, and the reaction was warmed to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid 76-11 (0.14 g, yield 84%).

MS(ESI, pos.ion) m/z: 800.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.37 (s, 1H), 9.05 (s, 1H), 8.41 (d, J=0.7Hz, 1H), 8.16 (d, J=6.9Hz, 1H), 7.69–7.51 (m, 2H), 7.24 (d, J=7.2Hz, 1H), 7.18–7.15 (m, 1H), 7.14–7.12 (m, 2H), 6.88 (dd, J=8.9, 2.0Hz, 1H), 6.83 (td, J=8.4, 2.4Hz, 1H), 5.94 (s, 1H), 5.74 (dd, J=18.1, 8.8Hz, 1H), 5.06–4.90 (m, 1H), 4.79–4.69 (m, 1H), 4.60 (t, J=7.6Hz, 1H), 4.48 (d, J=11.1Hz, 1H), 4.16 (dd, J=11.3, 4.5Hz, 1H), 2.94–2.86 (m, 1H), 2.62 (d, J=8.4Hz, 3H), 2.61–2.51 (m, 2H), 2.48 (dd, J=13.3, 5.8Hz, 1H), 2.30 (q, J=8.6Hz, 1H), 2.05 (dd, J=7.5, 4.5Hz, 1H), 1.94–1.91 (m, 2H), 1.82–1.72 (m, 1H), 1.63 (dd, J=9.2, 5.9Hz, 1H), 1.53–1.47 ( m, 4H), 1.38–1.32 (m, 2H), 1.17–1.06 (m, 3H), 0.92 (dd, J=8.3, 4.8 Hz, 1H) ppm. HPLC purity: 96.43%.

Example 77

synthetic route

Step 1: Synthesis of Compound 77-2

Compound 77-1 (944 mg, _3.1 mmol) was added to 100 mL of toluene, POCl (939 mg, 6.1 mmol) and N,N-dimethylaniline (185 mg, 1.5 mmol) were slowly added under stirring, and the temperature was raised to The reaction was carried out at 110°C for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 77-2 as a pale yellow solid (0.8 g, yield 80%).

Step 2: Synthesis of Compound 77-3

Compound N-Boc-4-(R)-hydroxyproline (1.5 g, 6.5 mmol) was dissolved in 50 mL of DMF, under ice bath, and NaH (60%, 520 mg, 13 mmol) was added thereto, after the addition was complete , the reaction solution was warmed to room temperature and stirred for 2 hours.

Compound 77-2 (2.1 g, 6.5 mmol) was dissolved in 10 mL of anhydrous DMF, the resulting mixture was added to the above solution, and the resulting reaction solution was further stirred for 4 hours. After the reaction, pour the reaction solution into 50 mL of water, adjust the pH to 2-3 with 1N HCl, then extract with ethyl acetate (20 mL×3), combine the organic phases, wash the organic phases with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, then filtered, and finally concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 77-3 (3.0 g, yield 90%).

MS(ESI, neg.ion) m/z: 518.9[M-1] ^- .

Step 3: Synthesis of Compound 77-4

Compound 77-3 (50 mg, 0.1 mmol), compound 1-9 (42 mg, 0.1 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to 15 mL of CH ₂ Cl ₂ in an ice bath DIPEA (48 mg, 0.37 mmol) was added thereto, and after the addition was completed, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the pH of the reaction solution was adjusted to about 2 with 1N hydrochloric acid, then the aqueous phase was extracted with dichloromethane (10 mL×2), the organic phases were combined, and then the organic phase was washed with saturated sodium chloride solution, and then washed with anhydrous sulfuric acid. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 77-4 (50 mg, yield 70%).

MS (ESI, pos.ion) m/z: 734.9 [M+H] ⁺ .

Step 4: Synthesis of Compound 77-6

Compound 77-4 (600 mg, 0.8 mmol) was dissolved in 5N HCl in 30 mL of ethyl acetate, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue (300 mg, 0.45 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , and compound 2-11 (223 mg, 0.49 mmol), EDCI (103 mg, 0.54 mmol) and HOAT (73 mg, 0.54 mmol) were added thereto, Additional DIPEA (177 mg, 1.3 mmol) was added under ice bath and the resulting mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 77-6 (0.34 g, 2:1) as a pale yellow solid. step yield 64%).

Step 5: Synthesis of Compound 77-7

Compound 77-6 (230 mg, 0.28 mmol) was dissolved in 300 mL of 1,2-dichloroethane, Jan's 1B catalyst (30 mg) was added under nitrogen protection, and the reaction solution was heated to 75°C for 48 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and the obtained crude product was purified by preparative HPLC to obtain compound 77-7 (160 mg, yield 73%) as a white solid.

MS (ESI, pos.ion) m/z: 859.3 [M+H] ⁺ .

Step 6: Synthesis of Compound: 77-8

Compound 77-7 (237 mg, 0.3 mmol) was dissolved in 5N HCl in 30 mL of ethyl acetate, and the reaction solution was stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a white solid compound 77-8 (0.2 g, two-step yield 90%).

Step 7: Synthesis of Compound 77-9

Compound 77-8 (110 mg, 0.14 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , to which was added compound 5-methylpyrazine-2-carboxylic acid (21 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) and HOAT (22 mg, 0.17 mmol) and DIPEA (54 mg, 0.42 mmol) were added under ice bath. The reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 77-9 (0.1 g, yield 80%).

MS(ESI, pos.ion) m/z: 878.2[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.33 (s, 1H), 9.04 (s, 1H), 8.41 (s, 1H), 8.14 (d, J=6.8 Hz, 1H), 7.60 (dt, J =45.5,22.8Hz,1H),7.47(d,J=22.4Hz,1H),7.40(d,J=2.3Hz,1H),7.23(dd,J=8.6,2.4Hz,1H),7.01(d , J=8.6Hz, 1H), 6.91–6.82 (m, 2H), 5.91 (s, 1H), 5.75 (dd, J=18.1, 8.7Hz, 1H), 5.06–4.96 (m, 1H), 4.76– 4.67(m, 1H), 4.60(t, J=7.7Hz, 1H), 4.53(d, J=11.5Hz, 1H), 4.12(dt, J=25.5, 12.8Hz, 1H), 2.96–2.87(m ,1H),2.64(s,3H),2.54(dd,J=19.5,11.8Hz,1H),2.52–2.46(m,1H),2.30(q,J=8.7Hz,1H),2.06(dd, J=23.8, 11.1Hz, 1H), 1.93 (dt, J=18.1, 9.1Hz, 2H), 1.84–1.76 (m, 2H), 1.62 (dd, J=9.3, 5.9Hz, 1H), 1.54–1.48 (m, 4H), 1.37 (dd, J=14.9, 9.3 Hz, 2H), 1.16-1.08 (m, 2H), 0.96-0.85 (m, 2H) ppm.

HPLC purity: 95.68%.

Example 78

synthetic route

Step 1: Synthesis of Compound 78-2

Compound 78-1 (944 mg, 3.1 mmol) was added to 100 mL of toluene, and POCl ₃ (939 mg, 6.1 mmol) and N,N-dimethylaniline (185 mg, 1.5 mmol) were slowly added with stirring. After the addition, the temperature of the reaction solution was raised to 110°C for 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 78-2 as a pale yellow solid (0.8 g, yield 80%).

Step 2: Synthesis of Compound 78-3

Compound N-Boc-4-(R)-hydroxyproline (1.5g, 6.5mmol) was dissolved in 50mL DMF solution, under ice bath, NaH (30% dispersed in mineral oil, 520mg, 13 mmol), after the addition was complete, the reaction was warmed to room temperature and stirred for 2 hours.

Compound 78-2 (2.1 g, 6.5 mmol) was dissolved in 10 mL of anhydrous DMF, then added to the above reaction solution, and then stirring was continued for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, the pH of the resulting mixture was adjusted to 2-3 with 1N aqueous HCl solution, and then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a pale yellow solid Compound 78-3 (3.0 g, 90% yield).

MS (ESI, pos.ion) m/z: 518.9 [M+H] ⁺ .

Step 3: Synthesis of Compound 78-4

Compound 78-3 (50 mg, 0.1 mmol), compound 2-11 (42 mg, 0.1 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to 15 mL of CH ₂ Cl ₂ under ice bath Additional DIPEA (48 mg, 0.37 mmol) was added. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the pH value of the reaction solution was adjusted to about 2 with 1N hydrochloric acid, then the aqueous phase was extracted with dichloromethane (10 mL×2), the organic phases were combined, and then the organic phase was washed with saturated sodium chloride, and then with anhydrous sodium sulfate. It was dried, then filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 78-4 (50 mg, yield 70%) as a pale yellow solid.

MS (ESI, pos.ion) m/z: 734.9 [M+H] ⁺ .

Step 4: Synthesis of Compound 78-6

Compound 78-4 (600 mg, 0.8 mmol) was dissolved in 5N HCl in 30 mL of ethyl acetate and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The obtained residue (300 mg, 0.45 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , compound 2-11 (223 mg, 0.49 mmol), EDCI (103 mg, 0.54 mmol) and HOAT (73 mg, 0.54 mmol) were added, under ice bath DIPEA (177 mg, 1.3 mmol) was added, then warmed to room temperature and stirred for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 78-6 (0.34 g, 2:1) as a pale yellow solid. step yield 64%).

Step 5: Synthesis of Compound: 78-7

Compound 78-6 (230 mg, 0.28 mmol) was dissolved in 300 mL of 1,2-dichloroethane, and under nitrogen protection, Jen's 1B catalyst (30 mg) was added to it, the temperature of the reaction solution was increased to 75 ° C, and the reaction 48 Hour. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 78-7 (160 mg, yield 73%) as a white solid.

MS (ESI, pos.ion) m/z: 859.3 [M+H] ⁺ .

Step 6: Synthesis of Compounds 78-8

Compound 78-7 (237 mg, 0.3 mmol) was dissolved in 30 mL of 5N HCl in ethyl acetate, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a white solid compound 78-8 (0.2 g, 90% in two-step yield).

Step 7: Synthesis of Compound 78-9

Compound 78-8 (110 mg, 0.14 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , and compound 5-methylisoxazole-3-carboxylic acid (21 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) were added thereto. and HOAT (22 mg, 0.17 mmol), and DIPEA (54 mg, 0.42 mmol) was added under an ice bath. The reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a pale yellow solid 78-9 (0.1 g, yield 80%) ).

MS(ESI, pos.ion) m/z: 867.2[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.39(s,1H), 7.98(s,1H), 7.73(s,1H), 7.61-7.46(m,1H), 7.28(s,1H), 7.26 –7.18(m,1H),7.01(d,J=8.5Hz,1H),6.93–6.86(m,1H),6.81(dd,J=11.3,4.8Hz,1H),6.20(s,1H), 5.91(s, 1H), 5.75(d, J=8.7Hz, 1H), 5.00(t, J=9.2Hz, 1H), 4.80(t, J=7.8Hz, 1H), 4.73–4.58(m, 2H ), 4.10(dd, J＝11.3, 3.7Hz, 1H), 2.92(d, J＝4.2Hz, 1H), 2.65(d, J＝4.4Hz, 3H), 2.42(s, 3H), 2.31(dd , J=16.8, 8.4Hz, 1H), 2.14 (dd, J=22.1, 10.5Hz, 1H), 1.91–1.84 (m, 2H), 1.69 (s, 1H), 1.50 (dd, J=13.8, 7.7 Hz, 5H), 1.31 (s, 2H), 1.20–1.07 (m, 2H), 0.93 (dd, J=18.6, 12.8 Hz, 2H) ppm.

HPLC purity: 95.17%.

Example 79

synthetic route

Step 1: Synthesis of Compound 79-2

Compound 79-1 (944 mg, 3.1 mmol) was added to 100 mL of toluene, and under stirring, POCl ₃ (939 mg, 6.1 mmol) and N,N-dimethylaniline (185 mg, 1.5 mmol) were slowly added. After the addition , the temperature of the reaction solution was raised to 110 °C for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 79-2 as a pale yellow solid (0.8 g, yield 80%).

Step 2: Synthesis of Compound 79-3

Compound N-Boc-4-(R)-hydroxyproline (1.5 g, 6.5 mmol) was dissolved in 50 mL of DMF, to which was added NaH (30% dispersed in mineral oil, 520 mg, 13 mmol) under ice bath . After the addition, the reaction solution was warmed to room temperature and stirred for 2 hours.

Compound 79-2 (2.1 g, 6.5 mmol) was dissolved in 10 ml of anhydrous DMF, and then added to the above reaction solution, and the reaction solution was continuously stirred for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, the pH of the resulting mixture was adjusted to 2-3 with 1N HCl, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and then the organic phase was washed with saturated sodium chloride solution washed, dried over anhydrous sodium sulfate, and then filtered,

The filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 79-3 (3.0 g, yield 90%) as a pale yellow solid ).

MS (ESI, pos.ion) m/z: 518.9 [M+H] ⁺ .

Step 3: Synthesis of Compound 79-4

Compound 79-3 (100 mg, 0.19 mmol), 4-methoxyphenylboronic acid (31 mg, 0.2 mmol), Pd(PPh ₃ ) ₄ (22 mg, 0.02 mmol) and K ₂ CO ₃ (180 mg, 0.58 mmol) were dissolved In a mixed solvent of THF (20 mL) and water (0.1 mL), the reaction solution was stirred at room temperature overnight.

After the reaction was completed, the reaction was quenched with saturated sodium chloride solution (20 mL), the resulting mixture was extracted with ethyl acetate (10 mL×3), and the organic phases were combined,

Then the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain yellow solid compound 79-4 (90 mg, yield 86%).

MS (ESI, pos.ion) m/z: 549.0 [M+H] ⁺ .

Step 4: Synthesis of Compound 79-5

Compound 79-4 (55 mg, 0.1 mmol), compound 1-9 (42 mg, 0.1 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to 15 mL of CH ₂ Cl ₂ under ice bath , and then DIPEA (48 mg, 0.37 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the pH value of the reaction mixture was adjusted to about 2 with 1N hydrochloric acid, then extracted with dichloromethane (10ml×2), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride, and then with anhydrous sodium sulfate. After drying, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 79-5 (50 mg, yield) as a pale yellow solid. rate 70%).

Step 5: Synthesis of Compound 79-7:

Compound 79-5 (580 mg, 0.76 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue (314 mg, 0.45 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , and compound 2-11 (223 mg, 0.49 mmol), EDCI (103 mg, 0.54 mmol) and HOAT (73 mg, 0.54 mmol) were added thereto on ice under the bath,

Additional DIPEA (177 mg, 1.3 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 4 hours. After the reaction, the solvent was evaporated under reduced pressure,

The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 79-7 as a pale yellow solid (0.34 g, yield 80%).

Step 6: Synthesis of Compound: 79-8

Compound 79-7 (453 mg, 0.5 mmol) was dissolved in 300 mL of 1,2-dichloroethane, and Jan's 1B catalyst (37 mg) was added thereto under nitrogen protection, and the reaction solution was heated to 75° C. for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 79-8 (0.3 g, yield 70%) as a white solid.

Step 7: Synthesis of Compound 79-9

Compound 79-8 (339 mg, 0.38 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a white solid compound 79-9 (0.29 g, yield 90%).

Step 8: Synthesis of Compounds 79-10

Compound 79-9 (123 mg, 0.14 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , to which was added compound 5-methylpyrazine-2-carboxylic acid (21 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) and HOAT (22 mg, 0.17 mmol), under ice bath, was added DIPEA (54 mg, 0.42 mmol), then the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid 79-10 (0.1 g, collected rate 80%).

MS(ESI, pos.ion) m/z: 906.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.39 (s, 1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.16 (d, J=6.6 Hz, 1H), 7.63 (dd, J =15.0,8.2Hz,2H),7.52(d,J=8.5Hz,2H),7.43(d,J=1.4Hz,1H),7.30(dd,J=8.3,1.6Hz,1H),7.17(d , J=8.3Hz, 1H), 6.96(d, J=8.5Hz, 2H), 6.93–6.87(m, 1H), 6.85(dd, J=11.3, 4.8Hz, 1H), 5.96(s, 1H) ,5.74(d,J＝9.1Hz,1H),5.01(t,J＝9.4Hz,1H),4.73(s,1H),4.61(t,J＝7.5Hz,1H),4.50(d,J＝ 11.2Hz, 1H), 3.84(s, 3H), 2.91(d, J=4.9Hz, 1H), 2.65–2.53(m, 5H), 2.49(dd, J=13.0, 6.0Hz, 1H), 2.31( dd, J＝17.0, 8.4Hz, 1H), 1.98–1.88(m, 2H), 1.78(s, 1H), 1.64(dd, J＝8.9, 5.9Hz, 1H), 1.49(d, J＝4.2Hz , 5H), 1.35 (s, 3H), 1.17–1.05 (m, 2H), 0.90 (ddd, J=22.0, 13.1, 7.0 Hz, 2H) ppm.

HPLC purity: 95.61%.

Example 80

synthetic route

Step 1: Synthesis of Compound 80-2

Compound 80-1 (4.4 g, 20 mmol), 4-methoxyphenylboronic acid (3.73 g, 22 mmol), Pd(PPh ₃ ) ₄ (0.7 g, 0.6 mmol) and K ₂ CO ₃ (13.8 g, 100 mmol) were combined Dissolved in a mixed solvent of THF (80 mL) and water (20 mL), the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated sodium chloride solution (200 mL), then the resulting mixture was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride solution, and then Dry over anhydrous sodium sulfate, then filter, and concentrate the filtrate under reduced pressure to obtain yellow solid compound 80-2 (4.8 g, yield 90%).

Step 2: Synthesis of Compound 80-4

Compounds 80-2 (1.0 g, 6 mmol) and 80-3 (1.6 g, 6 mmol) were dissolved in DMF (20 mL), K ₂ CO ₃ (1.66 g, 12 mmol) was added thereto, and the reaction solution was warmed to 110° C. React overnight. After the reaction was completed, 5 mL of water was added to quench the reaction, the pH of the resulting mixture was adjusted to about 2-3 with 1N hydrochloric acid solution, extracted with ethyl acetate (50 mL×3), and the combined organic phases were washed with saturated sodium chloride solution , then dried over anhydrous sodium sulfate, and then filtered. The obtained filtrate was concentrated under reduced pressure to obtain the crude product of compound 80-4 as an orange oily liquid, which was directly carried out to the next step.

MS(ESI, pos.ion) m/z: 416[M+H] ⁺ .

Step 3: Synthesis of Compound 80-5

The crude compound 80-4 was dissolved in 100 mL of glacial acetic acid, reduced iron powder (1.68 g, 30 mmol) was added, and the reaction solution was heated to 110° C. for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered again, the filtrate was concentrated, and the concentrated residue was poured into 200 mL of water, where a solid was precipitated and filtered. The filter cake was washed with water, and then dried to obtain yellow solid compound 80-5 (1.8 g, two-step yield 85%)

MS (ESI, pos.ion) m/z: 354 [M+H] ⁺ .

Step 4: Synthesis of Compound 80-6

Compound 80-5 (1.0 g, 2.74 mmol) was added to 20 mL of toluene, and under stirring, POCl ₍ 0.84 g, 5.48 mmol) and N,N-dimethylaniline (0.14 g, 1.13 mmol) were slowly added, After the addition, the temperature of the reaction solution was raised to 110°C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 80-6 as a pale yellow solid (950 mg, yield 93%). MS (ESI, pos.ion) m/z: 372 [M+H] ⁺ .

Step 5: Synthesis of Compound 80-7

Compound 2-7 (750 mg, 3.07 mmol) was dissolved in 20 mL of DMF, to which NaH (60% dispersed in mineral oil, 307 mg, 7.68 mmol) was added in portions under ice bath. After the addition, the reaction mixture was raised to room temperature and stirred for 30 minutes.

Compound 80-6 (950 mg, 2.56 mmol) was dissolved in 2 mL of DMF, then added to the above reaction system, and stirring was continued for 2 hours. After the reaction, the reaction solution was poured into 30 mL of water, the pH of the resulting mixture was adjusted to 2-3 with 1N HCl aqueous solution, and then extracted with ethyl acetate (50 mL×3), the organic phases were combined, and the combined organic phases were washed with saturated chlorinated water. Washed with sodium solution, dried over anhydrous sodium sulfate, then filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale Yellow solid compound 80-7 (920 mg, yield 62%).

MS (ESI, neg.ion) m/z: 565 [MH] ^- .

Step 6: Synthesis of Compound 80-8

Compound 80-7 (920 mg, 1.62 mmol), compound 1-9 (783 mg, 1.93 mmol), EDCI (402 mg, 2.11 mmol) and HOAT (260 mg, 1.93 mmol) were added to CH ₂ Cl ₂ (25 mL), ice DIPEA (0.85 mL, 4.86 mmol) was added thereto under the bath, and after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 80-8 (1.2 g , the yield is 95%).

MS (ESI, pos.ion) m/z: 779 [M+H] ⁺ .

Step 7: Synthesis of Compounds 80-10

Compound 80-8 (1.2 g, 1.54 mmol) was dissolved in 5N HCl in ethyl acetate (20 mL), the reaction solution was stirred at room temperature for 3 hours, and then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 20 mL of CH ₂ Cl ₂ , then compound 2-11 (683 mg, 1.52 mmol), EDCI (313 mg, 1.64 mmol) and HOAT (205 mg, 1.52 mol) were added, and DIPEA ( 0.7 mL, 3.78 mmol). The reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=3:1) to obtain a pale yellow solid compound 80-10 (1.0 g, yield 70%).

MS (ESI, neg.ion) m/z: 930 [MH] ^- .

Step 8: Synthesis of Compounds 80-11

Compound 80-10 (500 mg, 0.54 mmol) was dissolved in 100 mL of 1,2-dichloroethane, Grubbs II catalyst (50 mg) was added to it under nitrogen protection, and the reaction mixture was heated to 65° C. for 48 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 80-11 (330 mg, yield 68%) as a white solid.

MS(ESI, pos.ion) m/z: 904.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.38 (s, 1H), 7.42 (s, 1H), 7.37–7.28 (m, 5H), 7.19 (s, 1H), 7.12–7.00 (m, 2H) ,5.94(s,1H),5.73(dd,J＝17.7,8.7Hz,1H),5.27(s,1H),5.00(t,J＝9.4Hz,1H),4.79–4.52(m,2H), 4.40–4.32 (m, 1H), 4.09–4.00 (m, 1H), 3.94 (s, 3H), 2.92 (s, 1H), 2.74–2.52 (m, 3H), 2.40–2.28 (m, 1H), 1.99–1.81 (m, 4H), 1.67–1.52 (m, 2H), 1.42–1.26 (m, 14H), 1.18–1.09 (m, 2H), 0.97–0.87 (m, 2H) ppm.

HPLC purity: 97.23%.

Example 81

synthetic route

Step 1: Synthesis of Compound 81-1

Compound 35-9 (249 mg, 0.3 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL) and stirred at room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure to obtain a white solid compound 81-1 (0.2 g, yield 90%).

Step 2: Synthesis of Compound 81-2

Compound 81-1 (107 mg, 0.14 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , to which was added compound 5-methylpyrazine-2-carboxylic acid (21 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) and HOAT (22 mg, 0.17 mmol) was added DIPEA (54 mg, 0.42 mmol) under an ice bath. The reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 81-2 (0.1 g, yield) as a pale yellow solid. rate 80%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.31 (s, 1H), 9.04 (s, 1H), 8.38 (s, 1H), 8.15 (d, J=7.1 Hz, 1H), 7.69 (d, J= 8.1Hz, 1H), 7.44(s, 1H), 7.34(d, J=8.0Hz, 1H), 7.21–7.17(m, 3H), 5.98(s, 1H), 5.75(dd, J=18.0, 8.7 Hz, 1H), 5.02 (t, J=9.4Hz, 1H), 4.78 (t, J=7.2Hz, 1H), 4.69–4.49 (m, 2H), 4.15 (dd, J=11.4, 4.2Hz, 1H) ), 2.99–2.86 (m, 1H), 2.64 (s, 3H), 2.34 (d, J=8.6Hz, 1H), 2.07 (d, J=7.5Hz, 1H), 1.99–1.91 (m, 2H) ,1.72(s,4H),1.51(dd,J＝21.4,17.2Hz,5H),1.35(s,4H),1.13(ddd,J＝12.6,8.7,4.5Hz,2H),0.96–0.86(m , 2H)ppm.

Example 82

synthetic route

Step 1: Synthesis of Compound 82-1

Compound 35-9 (249 mg, 0.3 mmol) was dissolved in 5N HCl in 30 mL of ethyl acetate. The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was evaporated under reduced pressure to obtain compound 82-1 (0.2 g, yield 90%) as a white solid.

Step 2: Synthesis of Compound 82-2

Compound 82-1 (107 mg, 0.14 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , and then compound 5-methylisoxazole-3-carboxylic acid (21 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) were added thereto sequentially ) and HOAT (22 mg, 0.17 mmol), DIPEA (54 mg, 0.42 mmol) was added under an ice bath, and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 82-2 (0.1 g, yield) as a pale yellow solid. rate 80%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.30 (s, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.46 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.29(s, 1H), 7.19(td, J=5.8, 2.1Hz, 3H), 6.17(s, 1H), 5.97(s, 1H), 5.76(dd, J=17.8, 9.0Hz, 1H), 5.06 –4.97(m,1H),4.81-4.75(m,1H),4.64(dd,J=16.9,9.3Hz,2H),4.11(dd,J=11.5,4.0Hz,1H),2.97-2.91(m ,1H),2.69(dd,J＝7.7,4.6Hz,2H),2.62(s,1H),2.43(s,3H),2.31(q,J＝8.6Hz,1H),1.97–1.87(m, 2H), 1.51 (ddd, J=10.0, 8.4, 4.4Hz, 6H), 1.37–1.31 (m, 4H), 1.20–1.08 (m, 3H), 0.96 (d, J=7.7Hz, 1H), 0.90 (d, J=7.0 Hz, 1 H) ppm.

Example 83

synthetic route

Step 1: Synthesis of Compound 83-2

Compound 83-1 (710 mg, 3.1 mmol) was added to 100 mL of toluene, and under stirring, POCl ₃ (939 mg, 6.1 mmol) and N,N-dimethylaniline (185 mg, 1.5 mmol) were slowly added thereto, and the addition was complete. After that, the temperature of the reaction solution was raised to 110° C. to react for 5 hours. After the completion of the reaction, the reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain compound 83-2 (0.8 g, yield 80%) as a pale yellow solid.

Step 2: Synthesis of Compound 83-3

The compound N-Boc-4-(R)-hydroxyproline (1.6 g, 6.5 mmol) was dissolved in 50 mL of DMF solution, and NaH (30% dispersed in mineral oil, 520 mg, 13 mmol) was added thereto under ice bath. ), after the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours.

Compound 83-2 (2.1 g, 6.5 mmol) was dissolved in 10 mL of anhydrous DMF solution, and then added to the above reaction mixture, which was stirred for 4 hours. After the reaction was completed, the reaction mixture was poured into 50 mL of water, the pH of the resulting mixture was adjusted to 2-3 with 1N HCl aqueous solution, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the combined organic items were washed with saturated chlorinated water. Washed with sodium solution, then dried with anhydrous sodium sulfate, then filtered, the filtrate was concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale Yellow solid compound 83-3 (3.0 g, yield 90%).

Step 3: Synthesis of Compound 83-4

Compound 83-3 (44 mg, 0.1 mmol), compound 1-9 (42 mg, 0.1 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to 15 mL of CH ₂ Cl ₂ solution, ice bath DIPEA (48 mg, 0.37 mmol) was added at the next temperature, and after the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. After the reaction, adjust the pH value to about 2 with 1N hydrochloric acid solution, then extract with dichloromethane (10 mL×2), combine the organic phases, wash the combined organic phases with saturated sodium chloride, and then dry with anhydrous sodium sulfate , then filtered, the obtained filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 83-4 (50 mg, collected rate 70%).

Step 4: Synthesis of Compound 83-5

Compound 83-4 (524 mg, 0.8 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was evaporated under reduced pressure to remove the solvent. The residue (263 mg, 0.45 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , and compound 2-11 (223 mg, 0.49 mmol), EDCI (103 mg, 0.54 mmol) and HOAT (73 mg, 0.54 mmol) were added thereto on ice Under the bath, additional DIPEA (177 mg, 1.3 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 83-6 (0.34 g, yield) as a pale yellow solid. rate 64%).

Step 5: Synthesis of Compound 83-7

Compound 83-6 (226 mg, 0.28 mmol) was dissolved in 300 mL of 1,2-dichloroethane solution, Jan's 1B catalyst (30 mg) was added under nitrogen protection, and the temperature was raised to 75° C. to react for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to obtain compound 83-7 (160 mg, yield 73%) as a white solid.

MS (ESI, pos.ion) m/z: 780.9 [M+H] ⁺ .

Step 6: Synthesis of Compound 83-8

Compound 83-7 (234 mg, 0.3 mmol) was dissolved in 5N HCl in 30 mL of ethyl ethyl ester solution, and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a white solid compound 83-8 (0.2 g, yield 90%).

Step 7: Synthesis of Compound 83-9

Compound 83-8 (110 mg, 0.14 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ solution, and the intermediate 5-methylpyrazine-2-carboxylic acid (21 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) were added thereto. ) and HOAT (22 mg, 0.17 mmol), DIPEA (54 mg, 0.42 mmol) was added under ice bath, and the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, the reaction mixture was evaporated to remove the solvent under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 83-9 (0.1 g, yield 80%).

MS(ESI, pos.ion) m/z: 800.3M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.40 (s, 1H), 9.03 (s, 1H), 8.42 (s, 1H), 8.15 (d, J=5.9 Hz, 1H), 7.90 (s, 1H) ), 7.59(d, J＝7.2Hz, 1H), 7.35(s, 1H), 7.11(s, 3H), 6.93(d, J＝7.9Hz, 1H), 6.78(s, 1H), 5.89(s ,1H),5.72(d,J＝8.5Hz,1H),4.99(t,J＝9.0Hz,1H),4.71(s,1H),4.57(t,J＝6.7Hz,1H),4.45(d , J＝10.7Hz, 1H), 4.13(dd, J＝11.3, 7.9Hz, 1H), 2.89(s, 1H), 2.60(s, 3H), 2.43(d, J＝31.6Hz, 2H), 2.27 (d, J=8.2Hz, 1H), 2.03(s, 2H), 1.77(s, 1H), 1.67(s, 1H), 1.47(s, 5H), 1.33(d, J=7.6Hz, 3H) , 1.09(d, J=4.7Hz, 2H), 0.87(d, J=24.4Hz, 2H) ppm.

Example 84

synthetic route

Synthesis of Compound 84-1

Compound 92-9 (0.13 g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 20 mL of 30% concentration of hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 2 hours . After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 5-methylpyrazine-2-carboxylic acid (0.02g, 0.2mmol), EDCI (0.04g, 0.2mmol) and HOAT (0.03g, 0.2mmol) were added to a round-bottom flask under nitrogen protection At this time, 20 mL of dichloromethane was added, then the mixture was cooled to 0°C, and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (20 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then reduced It was concentrated under pressure, and the obtained residue was purified by silica gel column (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 84-1 (0.076 g, yield 58%).

MS(ESI, pos.ion) m/z: 800.3M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.31 (s, 1H), 9.05 (d, J=1.3 Hz, 1H), 8.40 (d, J=0.9 Hz, 1H), 8.14 (d, J=6.9 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J=7.9Hz, 1H), 7.26–7.22 (m, 2H), 7.20–7.11 (m, 3H), 7.05–6.99 (m, 1H) ,5.97-5.91(m,1H),5.73(d,J＝10.1Hz,1H),5.04-4.96(m,1H),4.77-4.70(m,1H),4.58(t,J＝7.7Hz,1H) ), 4.50 (d, J=11.5Hz, 1H), 4.14 (dd, J=11.4, 4.5Hz, 1H), 2.94–2.84 (m, 1H), 2.62 (s, 3H), 2.59–2.46 (m, 3H), 2.33–2.24 (m, 1H), 2.07–2.01 (m, 1H), 1.95–1.90 (m, 2H), 1.62–1.58 (m, 1H), 1.54–1.45 (m, 5H), 1.16– 1.05 (m, 3H), 0.91–0.83 (m, 4H) ppm.

HPLC purity: 96.91%.

Example 85

synthetic route

Synthesis of Compound 85-1

Compound 5-9 (0.12 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then 20 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 Hour. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 5-methylpyrazine-2-carboxylic acid (0.02g, 0.2mmol), EDCI (0.04g, 0.2mmol) and HOAT (0.03g, 0.2mmol) were added to a round-bottom flask under nitrogen protection At the same time, 20 mL of dichloromethane was added, the mixture was cooled to 0°C, and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then reduced It was concentrated under pressure, and the obtained crude product was purified by silica gel column (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 85-1 (0.080 g, yield 65%).

MS(ESI, pos.ion) m/z: 813[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.33 (s, 1H), 9.08 (d, J=43.5 Hz, 1H), 8.42 (s, 1H), 8.21 (d, J=32.1 Hz, 1H), 7.64–7.52 (m, 1H), 7.48–7.34 (m, 2H), 7.18–7.06 (m, 3H), 6.99–6.92 (m, 1H), 6.65 (d, J=10.5Hz, 2H), 5.96 ( s, 1H), 5.75 (d, J=9.5Hz, 1H), 5.07–4.97 (m, 1H), 4.80 (s, 1H), 4.61 (t, J=7.5Hz, 1H), 4.27–4.09 (m ,1H),3.23(s,3H),2.98–2.85(m,1H),2.64(s,3H),2.61–2.40(m,3H),2.37–2.25(m,1H),2.09–1.90(m , 4H), 1.57–1.48 (m, 4H), 1.20–1.09 (m, 3H), 0.95–0.87 (m, 4H) ppm.

HPLC purity: 95.49%.

Example 86

synthetic route

Step 1: Synthesis of Compound 86-2

Compound 86-0 (1.0 g, 7.1 mmol) and compound 86-1 (1.3 g, 7.6 mmol) were dissolved in 15 mL of DMF, and K ₂ CO ₃ (2.0 g, 14.2 mmol) was added thereto, and the reaction mixture was refluxed overnight . After the reaction was completed, it was cooled to room temperature, and 100 mL of ethyl acetate was added. The obtained mixture was washed with H ₂ O (100 mL×2) and once with 50 mL of saturated brine. The organic phase was dried with anhydrous Na ₂ SO ₄ , and then reduced It was concentrated under pressure to obtain yellow solid compound 86-2 (2.0 g, yield: 97%), which was used in the next reaction without further purification.

Step 2: Synthesis of Compound 86-3

Compound 86-2 (2.0 g, 6.9 mmol) was dissolved in 50 mL of glacial acetic acid, and reduced iron powder (1.9 g, 36 mmol) was added thereto,

The reaction mixture was warmed to 115°C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, the solid was removed by filtration, 100 ml of 1N HCl solution was added dropwise to the obtained filtrate, a large amount of white solid was precipitated, and the obtained white solid was filtered, and the obtained white solid was dried under vacuum to obtain a white solid compound 86-3 (0.87 g, Yield: 55%); the next reaction was carried out without further purification.

Step 3: Synthesis of Compound 86-4

Compound 86-3 (0.8 g, 3 mmol) was added to 20 mL of toluene, phosphorus oxychloride (0.6 mL, 7 mmol) was added to it under nitrogen protection, and then N,N-dimethylaniline (0.2 mL) was slowly added. , 1.4 mmol), the reaction mixture was warmed to 110° C. and reacted for 6 hours. After the reaction was completed, it was cooled to 0°C, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid compound 86-4 (0.8 g, 90% yield).

Step 4: Synthesis of Compound 86-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, under nitrogen protection at 0°C, and anhydrous compound 2-7 (0.86 g, 4 mmol) was added thereto. In a DMF solution (10 mL), the reaction solution was heated to 30°C and stirred for 2 hours. A solution (10 mL) of compound 86-4 (0.8 g, 3 mmol) in anhydrous tetrahydrofuran was added to the above reaction solution, followed by stirring overnight. After the reaction was completed, the reaction was quenched with 20 mL of water at 0 °C, the resulting mixture was washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the combined The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1), A white solid compound 86-5 was obtained (1.0 g, yield: 70%).

MS (ESI, neg.ion) m/z: 441 [MH] ^- .

Step 5: Synthesis of Compound 86-6

Compound 86-5 (1.0 g, 2.3 mmol), compound 1-9 (1.0 g, 2.5 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen Under protection, 30 mL of dichloromethane was added, then cooled to 0°C, then DIPEA (1.05 mL, 6.02 mmol) was added, and the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (20 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered , the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 86-6 (1.0 g, yield 66%) ).

MS (ESI, pro.ion) m/z: 655 [M+H] ⁺ .

Step 6: Synthesis of Compound 86-8

Compound 86-6 (1.0 g, 1.5 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 2 Hour. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 2-11 (0.74g, 1.6mmol), EDCI (0.34g, 1.8mmol) and HOAT (0.23g, 1.7mmol) were added to a round-bottomed flask, and under nitrogen protection, 20 mL of two Methyl chloride, at 0 °C, and finally DIPEA (0.7 mL, 4.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure , the obtained crude product was purified by silica gel column (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 86-8 (1.0 g, yield 90%).

MS (ESI, neg.ion) m/z: 806 [MH] ^- .

Step 7: Synthesis of Compound 86-9

Compound 86-8 (0.38 g, 0.47 mmol) was dissolved in 300 ml of 1,2-dichloroethane, and under nitrogen protection, 0.05 g of Grubbs second-generation catalyst was added, and the reaction mixture was heated to 65 ° C and stirred for 48 hours . After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 86-9 ( 0.22 g, yield: 60%). MS (ESI, pos.ion) m/z: 780 [M+H] ⁺ .

Step 8: Synthesis of Compounds 86-11

Compound 86-9 (0.13 g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then 20 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 Hour. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The resulting solid, compound 5-methylpyrazine-2-carboxylic acid (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, under nitrogen protection , and then 20 mL of dichloromethane was added, at 0 °C, and finally DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and reduced in pressure. It was concentrated, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 86-11 (0.082 g, yield 64%).

MS(ESI, pos.ion) m/z: 800[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.33 (s, 1H), 9.11 (d, J=1.0 Hz, 1H), 8.43 (s, 1H), 8.12 (d, J=6.3 Hz, 1H), 7.63(s, 1H), 7.45-7.40(m, 1H), 7.25(d, J=7.4Hz, 1H), 7.18-7.12(m, 3H), 7.10-7.03(m, 2H), 6.03(s, 1H), 5.76(d, J=9.3Hz, 1H), 5.07–4.99 (m, 1H), 4.69–4.60 (m, 2H), 4.57 (d, J=11.4Hz, 1H), 4.09 (dd, J = 11.4, 4.0Hz, 1H), 2.96–2.86 (m, 1H), 2.69–2.59 (m, 5H), 2.55–2.47 (m, 1H), 2.32–2.25 (m, 1H), 2.10–2.02 (m , 1H), 1.97–1.88 (m, 2H), 1.56–1.48 (m, 5H), 1.18–1.08 (m, 3H), 0.92–0.85 (m, 4H) ppm.

HPLC purity: 96.14%.

Example 87

synthetic route

Synthesis of Compound 87-1

Compound 5-10 (0.12 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, and 20 mL of 30% hydrochloric acid/ethyl acetate solution was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours . After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round bottom flask under nitrogen Under protection, another 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 87-1 (0.07 g, yield 58%).

MS(ESI, pos.ion) m/z: 802[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.36 (s, 1H), 7.99-7.74 (m, 1H), 7.62-7.53 (m, 1H), 7.45-7.29 (m, 2H), 7.18-7.05 ( m,3H),6.97(d,J=7.6Hz,1H),6.68(dd,J=10.7,2.3Hz,1H),5.93(d,J=23.5Hz,1H),5.75(dd,J=18.3 ,8.6Hz,1H),5.05–4.98(m,1H),4.84(s,1H),4.65(s,2H),4.12(s,1H),3.24(s,3H),2.93(s,1H) ,2.72–2.57(m,3H),2.48–2.37(m,3H),2.35–2.27(m,1H),2.12–2.00(m,1H),1.94–1.81(m,3H),1.79–1.68( m, 2H), 1.57–1.44 (m, 6H), 0.94–0.85 (m, 4H) ppm.

HPLC purity: 93.39%.

Example 88

synthetic route

Synthesis of Compound 88-1

Compound 24-7 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and 20 mL of a 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 Hour. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 5-methylpyrazine-2-carboxylic acid (0.02g, 0.2mmol), EDCI (0.04g, 0.2mmol) and HOAT (0.03g, 0.2mmol) were added to a round-bottom flask under nitrogen protection 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.1 mL, 0.6 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 88-1 (0.07 g, yield 54%) as a white solid.

MS(ESI, pos.ion) m/z: 876[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.34 (s, 1H), 9.05 (s, 1H), 8.38 (s, 1H), 8.17 (d, J=7.1 Hz, 1H), 7.57 (d, J =8.1Hz,1H),7.49–7.41(m,3H),7.31(d,J=1.4Hz,1H),7.25(s,1H),7.20(dd,J=8.1,1.5Hz,1H),7.17 –7.07(m, 5H), 5.97(s, 1H), 5.73(dd, J=18.1, 8.7Hz, 1H), 5.00(t, J=9.4Hz, 1H), 4.82–4.75(m, 1H), 4.64(t,J＝7.7Hz,1H),4.54(d,J＝11.4Hz,1H),4.15(dd,J＝11.4,4.4Hz,1H),3.65(d,J＝2.1Hz,1H), 2.95–2.84 (m, 1H), 2.64–2.54 (m, 5H), 2.31 (dd, J=17.4, 8.7Hz, 1H), 2.09–2.01 (m, 1H), 1.96–1.90 (m, 2H), 1.62–1.58 (m, 1H), 1.52–1.46 (m, 4H), 1.17–1.05 (m, 3H), 0.94–0.84 (m, 4H) ppm.

HPLC purity: 94.74.

Example 89

synthetic route

Synthesis of Compound 89-2

Compound 86-9 (0.13 g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then 20 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 Hour. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round bottom flask under nitrogen Under protection, another 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 89-1 (0.06 g, yield 47%).

MS(ESI, pos.ion) m/z: 789[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.41 (s, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.27 (d, J=7.5Hz, 1H), 7.22-7.14 (m ,4H),7.14–7.11(m,1H),7.10–7.04(m,1H),6.21(s,1H),5.98(s,1H),5.76(dd,J=17.3,9.4Hz,1H), 5.05–4.96 (m, 1H), 4.84–4.74 (m, 2H), 4.66 (t, J=8.1Hz, 1H), 4.08 (dd, J=11.5, 3.8Hz, 1H), 2.98–2.86 (m, 1H), 2.79–2.62 (m, 3H), 2.38 (s, 3H), 2.35 (d, J=8.3Hz, 1H), 2.27–2.16 (m, 1H), 1.91–1.82 (m, 2H), 1.57 -1.48(m,4H),1.18-1.05(m,3H),0.94-0.85(m,4H)ppm.

HPLC purity: 97.78%.

Example 90

synthetic route

Synthesis of Compound 90-2

Compound 24-7 (0.13 g, 0.15 mmol) was dissolved in 2 mL of ethyl acetate, 20 mL of 30% hydrochloric acid/ethyl acetate solution was added at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.02g, 0.2mmol), EDCI (0.04g, 0.2mmol) and HOAT (0.03g, 0.2mmol) were added to a round bottom flask, Under a nitrogen blanket, 20 mL of dichloromethane was added, and finally DIPEA (0.1 mL, 0.6 mmol) was added at 0°C. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered, It was then concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 90-1 (0.09 g, yield 69%).

MS(ESI, pos.ion) m/z: 865[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.38 (s, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.52-7.45 (m, 3H), 7.34 (d , J=1.7Hz, 1H), 7.28–7.26 (m, 1H), 7.21 (dd, J=8.1, 1.7Hz, 1H), 7.19–7.09 (m, 5H), 6.16 (s, J=0.8Hz, 1H), 5.97(d, J=3.0Hz, 1H), 5.78–5.68 (m, 1H), 5.03–4.95 (m, 1H), 4.89–4.81 (m, 1H), 4.67 (t, J=7.8Hz) ,1H),4.59(d,J＝11.5Hz,1H),4.14(dd,J＝11.5,4.3Hz,1H),2.95-2.88(m,1H),2.70-2.57(m,3H),2.34( s, J=0.6Hz, 3H), 2.18–2.09 (m, 1H), 1.93–1.72 (m, 4H), 1.52–1.46 (m, 4H), 1.20–1.03 (m, 3H), 0.93–0.81 ( m,4H)ppm.

HPLC purity: 98.19%.

Example 91

synthetic route

Synthesis of Compound 91-1

Compound 92-9 (0.13 g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, 20 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 Hour. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.02g, 0.2mmol), EDCI (0.04g, 0.2mmol) and HOAT (0.03g, 0.2mmol) were added to a round bottom flask, Under nitrogen, another 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. , and then concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 91-1 (0.06 g, yield 47%).

MS(ESI, pos.ion) m/z: 789.2M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.38 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.73 (s, 1H), 7.28-7.24 (m, 2H), 7.21-7.13 (m, 4H), 6.98–6.91 (m, 1H), 6.13 (d, J=0.6Hz, 1H), 5.93 (d, J=3.3Hz, 1H), 5.77–5.69 (m, 1H), 4.99 ( dd, J=10.0, 8.7Hz, 1H), 4.84–4.77 (m, 1H), 4.70–4.60 (m, 2H), 4.10 (dd, J=11.5, 4.1Hz, 1H), 2.95–2.88 (m, 1H), 2.69–2.60 (m, 3H), 2.39 (s, 3H), 2.31 (q, J=8.8Hz, 1H), 2.16 (d, J=12.5Hz, 1H), 1.87–1.82 (m, 2H) ), 1.50–1.45 (m, 4H), 1.18–1.04 (m, 3H), 0.94–0.85 (m, 4H) ppm.

HPLC purity: 98.12%.

Example 92

synthetic route

Step 1: Synthesis of Compound 92-2

Compound 92-0 (1.0 g, 7.1 mmol) and compound 92-1 (1.3 g, 7.6 mmol) were dissolved in 15 mL of DMF, and K ₂ CO ₃ (2.0 g, 14.2 mmol) was added thereto, and the reaction mixture was refluxed overnight . After the reaction, the reaction system was cooled to room temperature, diluted with 100 mL of EtOAc, washed twice with 100 mL of H ₂ O, and the organic phase was washed once with 50 mL of saturated brine, dried over anhydrous Na ₂ SO ₄ , and then filtered. Concentration under reduced pressure gave yellow solid compound 92-2 (2.0 g, yield: 97%), which was directly carried out to the next reaction without further purification.

Step 2: Synthesis of Compound 92-3

Compound 92-2 (2.0 g, 6.9 mmol) was dissolved in 50 mL of glacial acetic acid, then reduced iron powder (1.9 g, 36 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, the solid was removed by filtration, 1N HCl solution was added dropwise to the filtrate, and a large amount of white solid was precipitated, which was then filtered, and the obtained solid was dried under vacuum to obtain a white solid compound 92-3 (0.87 g). , Yield: 55%), directly proceed to the next step without further purification.

Step 3: Synthesis of Compound 92-4

Compound 92-3 (0.8 g, 3 mmol) was added to 20 mL of toluene, under nitrogen protection, phosphorus oxychloride (0.6 mL, 7 mmol) was added, and finally N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added mmol). After the addition was complete, the reaction mixture was warmed to 110°C and reacted for 6 hours. After the completion of the reaction, the reaction solution was cooled to 0° C., and then concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 92- 4 (0.8 g, yield: 90%).

Step 4: Synthesis of Compound 92-5

Sodium hydride (60% dispersed in mineral oil, 0.45 g, 11 mmol) was added to 20 mL of anhydrous DMF, and under nitrogen protection at 0 °C, 10 mL of anhydrous compound 2-7 (0.92 g, 4 mmol) was added. DMF solution. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 2 hours.

A solution of compound 92-4 (0.8 g, 3 mmol) in anhydrous tetrahydrofuran (5 mL) was added to the above reaction solution, and the reaction mixture was continued to stir overnight. After the reaction was completed, the reaction was quenched with 20 mL of water at 0°C, washed with 20 mL of ethyl acetate, the aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and combined The organic phase. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1), A white solid compound 92-5 was obtained (1.0 g, yield: 70%).

MS (ESI, neg.ion) m/z: 441 [MH] ^- .

Step 5: Synthesis of Compound 92-6

Compound 92-5 (1.0 g, 2.3 mmol), compound 1-9 (1.0 g, 2.5 mmol), EDCI (0.5 g, 3.0 mmol) and HOAT (0.33 g, 2.4 mmol) were added to a round bottom flask under nitrogen Under protection, another 30 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (1.05 mL, 6.02 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 92-6 (1.0 g, yield 66%).

MS (ESI, neg.ion) m/z: 653.2 [MH] ^- .

Step 6: Synthesis of Compound 92-8

Compound 92-6 (1.0 g, 1.5 mmol) was dissolved in 2 mL of ethyl acetate, and 20 mL of 30% hydrochloric acid/ethyl acetate solution was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours . After the reaction, the reaction solution was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The resulting solid, compound 2-11 (0.74 g, 1.6 mmol), EDCI (0.34 g, 1.8 mmol) and HOAT (0.23 g, 1.7 mmol) were added to a round-bottomed flask, and 20 mL of dichloride was added under nitrogen protection. Methane, at 0 °C, and finally DIPEA (0.7 mL, 4.0 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered , the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 92-8 (1.0 g, yield 90%).

MS (ESI, neg.ion) m/z: 806 [MH] ^- .

Step 7: Synthesis of Target 92-9

Compound 92-8 (0.38 g, 0.47 mmol) was dissolved in 300 mL of 1,2-dichloroethane, 0.05 g of Grubbs second-generation catalyst was added under nitrogen protection, the reaction mixture was heated to 65° C. and stirred for 48 hours. After the reaction, the reaction system was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 92-9 after purification. (0.22 g, yield: 60%).

MS(ESI, pos.ion) m/z: 780[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.35-7.20 (m, 2H), 7.18-7.12 (m, 3H), 7.10-7.02 (m, 2H), 7.02-6.94 (m, 1H), 5.82 ( s, 1H), 5.60 (s, 1H), 5.40–5.17 (m, 1H), 5.11–4.88 (m, 1H), 4.66–4.51 (m, 1H), 4.48–4.19 (m, 2H), 4.04– 3.92 (m, 1H), 2.78 (s, 1H), 2.55 (s, 3H), 1.88–1.73 (m, 3H), 1.33–1.20 (m, 16H), 1.09–0.91 (m, 3H), 0.87– 0.76(m,4H)ppm.

HPLC purity: 97.40%.

Example 93

synthetic route

Step 1: Synthesis of Compound 93-1

Compound 26-9 (0.2 g, 0.3 mmol), compound 93-0 (0.1 g, 0.4 mmol), EDCI (0.08 g, 0.4 mmol) and HOAT (0.05, 0.4 mmol) were added to a round bottom flask under nitrogen protection Then, 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.15 mL, 1 mmol) was added. After the addition, the reaction solution was warmed to 30°C and stirred for 4 hours. After the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 93-1 (0.24 g, yield 89%).

MS (ESI, neg.ion) m/z: 901.3 [MH] ^- .

Step 2: Synthesis of Target 93-2

Compound 93-1 (0.2 g, 0.2 mmol) was dissolved in 200 mL of 1,2-dichloroethane, and 0.02 g of Jane's 1B catalyst was added under nitrogen protection. After the addition was complete, the reaction mixture was warmed to 65°C and stirred for 48 hours. After the reaction, the reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 93-2 (0.085 g, yield: 43%).

MS(ESI, pos.ion) m/z: 875[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.41 (s, 1H), 7.75-7.62 (m, 1H), 7.40 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.01 (d , J＝10.5Hz, 2H), 6.86(t, J＝8.5Hz, 2H), 5.93(s, 1H), 5.80–5.69(m, 1H), 4.99(t, J＝9.4Hz, 1H), 4.91 (d, J=7.0Hz, 1H), 4.59 (t, J=7.5Hz, 1H), 4.52 (d, J=11.2Hz, 1H), 4.40 (t, J=7.1Hz, 1H), 4.04 (dd , J=11.2, 4.4Hz, 1H), 3.33–3.23 (m, 2H), 3.23–3.12 (m, 2H), 2.95–2.86 (m, 1H), 2.65–2.50 (m, 3H), 2.28–2.18 (m, 1H), 1.95–1.86 (m, 2H), 1.84–1.72 (m, 3H), 1.50–1.41 (m, 9H), 1.18–1.05 (m, 3H), 0.98–0.74 (m, 4H) ppm.

HPLC purity: 93.46%.

Example 94

synthetic route

Synthesis of Compound 94-1

Compound 2-13 (0.13 g, 0.17 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, then 2 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 Hours. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 4 mL of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.03g, 0.23mmol), EDCI (0.12g, 0.61mmol) and HOAT (0.1g, 0.7mmol) were added to a round bottom flask, Under nitrogen, an additional 10 mL of dichloromethane was added, then cooled to 0°C, and DIPEA (0.2 mL, 1.0 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with dichloromethane (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 94-1 (0.110 g, yield 77%) .

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.03 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.44 (dd, J=7.8, 1.6 Hz, 1H), 7.39 (tt, J = 4.3, 2.2Hz, 1H), 7.28–7.26 (m, 1H), 7.18–7.15 (m, 3H), 7.15–7.12 (m, 1H), 6.13 (d, J=0.7Hz, 1H), 5.95 ( d, J=3.3Hz, 1H), 5.75 (dd, J=18.4, 8.5Hz, 1H), 5.03–4.98 (m, 1H), 4.88–4.82 (m, 1H), 4.70–4.62 (m, 2H) ,4.13(dd,J＝11.5,4.2Hz,1H),2.95–2.89(m,1H),2.66(dd,J＝7.9,3.6Hz,3H),2.38(s,3H),2.32(q,J ＝8.7Hz,1H),2.17(dd,J＝24.1,11.4Hz,1H),2.08–2.03(m,1H),1.87(ddd,J＝14.0,8.9,5.2Hz,2H),1.69(ddd, J=17.0, 8.1, 4.0 Hz, 1H), 1.54–1.46 (m, 5H), 1.13 (dtdd, J=15.5, 13.0, 7.6, 5.3 Hz, 3H), 0.96–0.87 (m, 3H) ppm.

HPLC purity: 97.05%.

Example 95

synthetic route

Step 1: Synthesis of Compound 95-1

Compound 58-7 (0.5 g, 0.83 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, 5 mL of 30% hydrochloric acid/ethyl acetate solution was added, and the reaction mixture was stirred at room temperature for 2 Hour. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 95-0 (0.25 g, 0.9 mmol), EDCI (0.1.5 g, 1 mmol) and HOAT (0.2 g, 1 mmol) were added to a round-bottomed flask, under nitrogen protection, and then 10 ml of dichloromethane were added. Methane, at 0 °C, and DIPEA (0.6 mL, 3.0 mmol) was added last. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered , the obtained filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 95-1 (0.4 g, yield 55.86%) ).

MS(ESI, pos.ion) m/z: 864.6 [M+H] ⁺ .

Step 2: Synthesis of target compound 95-2

Compound 95-1 (0.4 g, 0.46 mmol) was dissolved in 400 mL of 1,2-dichloroethane, and 0.05 g of Grubbs second-generation catalyst was added thereto under nitrogen protection. After the addition was complete, the reaction mixture was warmed to 65°C and stirred for 48 hours. After the reaction was completed, the reaction system was cooled to room temperature, and then concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 95-2 ( 0.25 g, yield: 65.78%).

MS(ESI, pos.ion) m/z: 835.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.64 (dd, J=8.2, 6.7 Hz, 1H), 7.55 (s, 1H), 7.13 (t, J=11.9 Hz, 1H), 6.88-6.81 (m ,2H),6.74–6.65(m,2H),5.92(s,1H),5.71(dd,J=17.5,8.5Hz,1H),5.10–4.99(m,2H),4.62(t,J=7.3 Hz, 1H), 4.51–4.40 (m, 2H), 4.08 (dd, J=11.1, 4.4Hz, 1H), 4.01 (q, J=6.9Hz, 2H), 3.34–3.28 (m, 2H), 3.24 –3.18(m, 2H), 2.88(s, 1H), 2.63 – 2.51(m, 3H), 2.23(dd, J=16.9, 8.4Hz, 1H), 1.96 – 1.79(m, 3H), 1.64(d , J=12.1Hz, 1H), 1.58–1.53 (m, 3H), 1.50–1.40 (m, 11H), 1.34–1.29 (m, 3H), 1.16–1.11 (m, 1H), 1.07 (d, J = 6.3 Hz, 1H), 0.95-0.86 (m, 2H) ppm.

HPLC purity: 96.18%.

Example 96

synthetic route

Step 1: Synthesis of Compound 96-2

Compound 96-0 (3.3 g, 15 mmol), compound 96-1 (2.5 g, 16 mmol), H ₂ O (25 mL), toluene (25 mL), potassium acetate (4.14 g, 29.7 mmol) and tetrakis(triphenylene) were combined Phosphine)palladium (0.5 g, 0.4 mmol) was added to a round bottom flask. Under nitrogen, the reaction mixture was stirred at 100°C for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, and the organic solvent was spin-dried under reduced pressure. Then 50 mL of water was added to dilute, and extracted with ethyl acetate (50 mL×2), and the organic phases were combined. The combined organic phases were washed once with 50 mL of saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered, and the filtrate was concentrated under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain a pale yellow solid product 96-2 (2.7 g, yield: 73%).

MS (ESI, pos.ion) m/z: 248.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 96-4

Compound 96-2 (2.94 g, 11.89 mmol) and compound 96-3 (2 g, 12.0 mmol) were dissolved in 60 mL of DMF, and K ₂ CO ₃ (6 g, 42.97 mmol) was added thereto. After the addition was complete, the reaction mixture was warmed to 90°C and stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (100 mL×2), the organic phases were combined, the combined organic phases were washed with 50 mL of saturated brine, and then washed with anhydrous Na ₂ SO ₄ It was dried and then filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 96-4 (4.6 g, yield: 93%).

Step 3: Synthesis of Compound 96-5

Compound 96-4 (4.5 g, 12 mmol) was dissolved in 90 mL of glacial acetic acid, and reduced iron powder (4.5 g, 81 mmol) was added thereto. After the addition was complete, the reaction mixture was warmed to 115°C and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, then the solid was removed by filtration, and 1N HCl solution (100 mL) was added to the obtained filtrate to precipitate a large amount of white solid, which was then filtered, and the obtained solid was heated to dryness under vacuum to obtain a white solid compound 96 -5 (4.0 g, yield: 100%), the next reaction was directly carried out without further purification.

MS (ESI, pos.ion) m/z: 318.9 [M+H] ⁺ .

Step 4: Synthesis of Compound 96-6

Compound 96-5 (1.0 g, 3.15 mmol) was added to 20 mL of toluene, under nitrogen protection, phosphorus oxychloride (1 mL, 10.62 mmol) was added, and N,N-dimethylaniline (0.2 mL, 10.62 mmol) was added slowly at last. 1.4 mmol). After the addition was complete, the reaction mixture was warmed to 110°C and stirred for 6 hours. After the completion of the reaction, the reaction mixture was cooled to 0°C, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 96 -6 (0.8 g, 80.00%).

MS (ESI, pos.ion) m/z: 337.1 [M+H] ⁺ .

Step 5: Synthesis of Compound 96-8

Potassium tert-butoxide (0.10 g, 0.9 mmol), compound 96-6 (0.2 g, 0.6 mmol) and compound 96-7 (0.2 g, 0.4 mmol) were added to 20 mL of anhydrous DMF. After the addition was complete, the reaction mixture was warmed to 40°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 20 mL of water, and then rinsed with 20 mL of ethyl acetate. The pH of the aqueous phase was adjusted to about 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, then filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1 ) was purified to give white solid compound 96-8 (0.19 g, yield: 60%)

MS (ESI, pos.ion) m/z: 869.0 [M+H] ⁺ .

Step 6: Synthesis of Compound 96-9

Compound 96-8 (0.19 g, 0.24 mmol) was dissolved in 2 mL of ethyl acetate, 30% hydrochloric acid/ethyl acetate solution (2 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours . After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.05g, 0.4mmol), EDCI (0.13g, 2.8mmol) and HOAT (0.1g, 3.0mmol) were added to a round bottom flask, Under nitrogen, another 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.5 mL, 10 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with dichloromethane (20 mL×2), and the organic phases were combined. The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2 : 1) Purification to obtain white solid compound 96-9 (0.168 g, yield 81%).

MS(ESI, pos.ion) m/z: 878.0 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.09 (d, J=7.9 Hz, 1H), 7.93 (s, 1H), 7.54-7.52 (m, 2H), 7.48-7.45 (m, 2H), 7.40 (td, J=8.2, 1.6Hz, 1H), 7.31 (dd, J=8.3, 2.3Hz, 1H), 7.19 (dd, J=14.0, 4.5Hz, 2H), 7.06–7.02 (m, 1H), 6.98–6.96 (m, 2H), 6.16 (d, J=0.6Hz, 1H), 5.97 (s, 1H), 5.74 (dd, J=18.1, 8.6Hz, 1H), 5.02–4.98 (m, 1H) ,4.88–4.83(m,1H),4.71–4.66(m,2H),4.13(dd,J=11.5,4.1Hz,1H),3.85(s,3H),2.94–2.90(m,1H),2.70 –2.63(m, 3H), 2.37(s, 3H), 2.32(t, J=8.5Hz, 1H), 2.18(dd, J=23.8, 11.3Hz, 1H), 2.05(d, J=11.0Hz, 1H), 1.86 (ddd, J=13.9, 8.9, 5.3Hz, 2H), 1.71–1.65 (m, 1H), 1.50–1.44 (m, 4H), 1.19–1.00 (m, 3H), 0.98–0.74 ( m,3H)ppm.

HPLC purity: 91.60%.

Example 97

synthetic route

Step 1: Synthesis of Compound 97-2

Compound 97-0 (1 g, 5.02 mmol) and compound 97-1 (1 g, 6.57 mmol) were dissolved in 20 mL of DMF, and K ₂ CO ₃ (4 g, 28.64 mmol) was added thereto. The reaction mixture was stirred at 90°C overnight. After the reaction, the reaction mixture was cooled to room temperature, diluted with 20 mL of EtOAc, washed with H ₂ O (20 mL×2), and washed with 50 mL of saturated brine once. The organic phase was dried over anhydrous Na ₂ SO ₄ , then filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 97-2 (1.4 g, yield: 84%), which was directly carried out to the next step without further purification.

Step 2: Synthesis of Compound 97-3

Compound 97-2 (1.4 g, 4.23 mmol) was dissolved in 20 mL of glacial acetic acid, then reduced iron powder (4.0 g, 71 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, then the solid was removed by filtration, and 1N HCl solution (50 mL) was added to the obtained filtrate to precipitate a large amount of white solid, which was filtered again, and the obtained white solid was dried under vacuum to obtain a white solid compound 97-3 (0.8 g, yield: 70%) was directly carried out to the next step without further purification.

MS (ESI, pos.ion) m/z: 270.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 97-4

Compound 97-3 (0.8 g, 2.97 mmol) was added to 20 mL of toluene, under nitrogen protection, phosphorus oxychloride (1 mL, 10.62 mmol) was added, and then N,N-dimethylaniline (0.2 mL, 10.62 mmol) was added slowly 1.4 mmol). After the addition, the temperature of the reaction solution was raised to 110°C and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to 0° C. and concentrated under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid compound 97- 4 (0.24 g, yield: 30%).

MS (ESI, pos.ion) m/z: 288.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 97-6

Potassium tert-butoxide (0.10 g, 0.9 mmol), compound 97-4 (0.24 g, 0.83 mmol) and compound 97-5 (0.2 g, 0.4 mmol) were added to 20 mL of anhydrous DMF. After the addition, the reaction The mixture was warmed to 40°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 20 mL of water, washed once with 20 mL of ethyl acetate, the pH of the aqueous phase was adjusted to about 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20 mL×3), and the organic compounds were combined. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V) )=2:1) and purified to obtain compound 97-6 as a white solid (0.24 g, yield: 90%).

MS (ESI, pos.ion) m/z: 820.3 [M+H] ⁺ .

Step 5: Synthesis of Compound 97-7

Compound 97-6 (0.22 g, 0.26 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, then a 30% concentration of hydrochloric acid/ethyl acetate solution (2 mL) was added, and the reaction mixture was stirred at room temperature for 2 Hours. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.05g, 0.4mmol), EDCI (0.13g, 2.8mmol) and HOAT (0.1g, 3.0mmol) were added to a round bottom flask, Under nitrogen, another 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.5 mL, 10 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, then taken with dichloromethane (20 mL×2), the organic phases were combined, the combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. , and then concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 97-7 (0.196 g, yield 81%).

MS(ESI, pos.ion) m/z: 829.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.12 (d, J=7.9 Hz, 1H), 7.94 (s, 1H), 7.42 (dd, J=7.7, 1.3 Hz, 1H), 7.39-7.34 (m ,1H),7.12(t,J＝8.3Hz,1H),7.05(t,J＝7.4Hz,1H),7.00(t,J＝7.5Hz,1H),6.79(d,J＝2.9Hz,1H) ), 6.65(dd, J＝8.8, 2.9Hz, 1H), 6.14(s, 1H), 5.94(s, 1H), 5.75(dd, J＝17.9, 8.8Hz, 1H), 5.02–4.98(m, 1H), 4.87–4.82 (m, 1H), 4.66 (dd, J=17.1, 9.4Hz, 2H), 4.55–4.49 (m, 1H), 4.14–4.09 (m, 1H), 2.94–2.89 (m, 1H), 2.70–2.62 (m, 3H), 2.38 (d, J=7.0Hz, 3H), 2.34–2.30 (m, 1H), 2.19 (dd, J=23.9, 11.1Hz, 1H), 1.85 (ddd , J=13.9, 8.9, 5.3Hz, 2H), 1.71–1.65 (m, 1H), 1.55–1.42 (m, 6H), 1.33 (d, J=6.0Hz, 6H), 1.22–1.07 (m, 3H) ), 0.96–0.84 (m, 2H) ppm.

HPLC purity: 91.65%.

Example 98

synthetic route

Step 1: Synthesis of Compound 98-1

Compound 98-0 (0.5 g, 1.49 mmol) was added to 10 mL of toluene, under nitrogen protection, phosphorus oxychloride (0.5 mL, 5.31 mmol) was added, and then N,N-dimethylaniline (0.1 mL) was slowly added , 0.7 mmol). After the addition, the temperature of the reaction solution was raised to 110° C. and stirred for 6 hours. After the reaction was completed, the reaction solution was cooled to 0° C., and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain pale yellow solid product 98 -1 (0.11 g, yield: 20%).

Step 2: Synthesis of Compound 98-3

Potassium tert-butoxide (0.10 g, 0.9 mmol), compound 98-1 (0.11 g, 0.3 mmol) and compound 98-2 (0.15 g, 0.26 mmol) were added to 15 mL of anhydrous DMF. After the addition was complete, the reaction mixture was warmed to 40°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 20 mL of water, the obtained mixture was washed once with 20 mL of ethyl acetate, the separated aqueous phase was adjusted to pH value of about 4 with 1N hydrochloric acid solution, and then extracted with ethyl acetate (20 mL×3), Combine the organic phases. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2 : 1) Purification to obtain white solid compound 98-3 (0.12 g, yield: 51%).

MS (ESI, pos.ion) m/z: 887.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 98-4

Compound 98-3 (0.12 g, 0.13 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, then a 30% concentration of hydrochloric acid/ethyl acetate solution (2 mL) was added, and the reaction mixture was stirred at room temperature for 2 Hours. After the reaction was completed, it was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate.

The white solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.05g, 0.4mmol), EDCI (0.13g, 2.8mmol) and HOAT (0.1g, 3.0mmol) were added to a round bottom flask, Under nitrogen, another 20 mL of dichloromethane was added, then cooled to 0°C, and finally DIPEA (0.5 mL, 10 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, and then extracted with dichloromethane (20 mL×2), and the organic phases were combined. The combined organic phases were washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) Purification gave compound 98-4 as a white solid (0.080 g, 67% yield).

MS(ESI, pos.ion) m/z: 895.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.38 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.55 (dd, J=8.6, 5.4 Hz, 2H ),7.42(dd,J＝10.5,5.5Hz,2H),7.19(d,J＝8.3Hz,1H),7.12(t,J＝8.6Hz,2H),6.72(d,J＝2.4Hz,1H ),6.62(dd,J＝8.7,2.4Hz,1H),6.23(s,1H),5.96(d,J＝3.0Hz,1H),5.75(dd,J＝18.0,8.8Hz,1H),5.02 –4.98(m,1H),4.88–4.82(m,1H),4.67(t,J=7.8Hz,1H),4.58(d,J=11.4Hz,1H),4.13(dd,J=11.4,4.2 Hz, 1H), 3.82 (s, 3H), 2.97–2.90 (m, 1H), 2.69–2.62 (m, 3H), 2.42 (s, 3H), 2.34–2.30 (m, 1H), 1.91–1.86 ( m, 2H), 1.70 (d, J=9.0Hz, 1H), 1.54–1.45 (m, 6H), 1.19–1.08 (m, 3H), 0.97–0.85 (m, 4H) ppm.

HPLC purity: 96.28%.

Example 99

synthetic route

Step 1: Synthesis of Compound 99-2

Compound 99-0 (8.1 g, 14 mmol), CDI (5 g, 30 mmol) and dichloromethane (80 mL) were added to a round bottom flask, the reaction solution was stirred at room temperature for 3 hours, and then DBU (5.1 g, 33 mmol) was added and compound 99-1 (4 g, 29.6 mmol), stirred at room temperature overnight. After the reaction was completed, 80 mL of 1M hydrochloric acid was added to quench the reaction, extracted and separated, the aqueous phase was extracted once more with dichloromethane (40 mL), and the organic phases were combined. The organic phase was washed once with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was spin-dried under reduced pressure. After spin drying, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 99-2 (2.3 g, yield: 24%) as a pale yellow solid.

MS (ESI, pos.ion) m/z: 697.4 [M+H] ⁺ .

Step 2: Synthesis of Compound 99-3

Compound 99-2 (2 g, 2.9 mmol), TBAF (6 mL, 5.74 mmol) and tetrahydrofuran (20 mL) were added to the round bottom flask, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, the organic solvent was spin-dried under reduced pressure, and the crude product obtained after spin-drying was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 99-3 (1.62 g, 96.9% yield).

MS (ESI, pos.ion) m/z: 583.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 99-5

Compound 99-3 (0.25 g, 0.43 mmol), compound 99-4 (0.25 g, 0.68 mmol), potassium tert-butoxide (0.3 g, 3 mmol) and DMF (20 mL) were added to the reaction flask, and the reaction solution was heated to 50 Stir overnight at °C. After the reaction was completed, 1 mol/L hydrochloric acid (20 mL) was added to quench the reaction, then ethyl acetate (20 mL) was added to dilute, and extraction was performed. The aqueous phase was extracted once with ethyl acetate (20 mL), and the organic phases were combined. Washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=4:1) to obtain Light yellow solid compound 99-5 (0.140 g, 36% yield).

MS(ESI, pos.ion) m/z: 912.4 [M+H] ⁺ .

Step 4: Synthesis of Compound 99-7

Compound 99-5 (0.13 g, 0.15 mmol) was dissolved in 2 mL of isopropanol, cooled to 0° C., then 5 mL of 40% concentration of hydrochloric acid in isopropanol was added, and the reaction mixture was stirred at room temperature for two hours. After the reaction was completed, it was filtered, and the obtained white solid was washed with 5 mL of ethyl acetate, and then dried in vacuo. The solid obtained after drying and compound 99-6 (0.05 g, 0.4 mmol), EDCI (0.07 g, 0.4 mmol) and HOAT (0.05 g, 0.4 mmol) were added to a round-bottomed flask, and 10 ml of two were added under nitrogen protection. Chloromethane was then cooled to 0°C, DIPEA (0.1 mL, 0.6 mmol) was added and the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, taken with dichloromethane (10 mL×2), the organic phases were combined, the organic phases were washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 99-7 (0.074 g, yield 52%).

MS(ESI, pos.ion) m/z: 921.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.31 (s, 1H), 8.05 (t, J=11.7 Hz, 1H), 7.80 (s, 1H), 7.54 (d, J=8.7 Hz, 2H), 7.45(t,J＝4.8Hz,1H),7.39(d,J＝8.7Hz,1H),7.30–7.26(m,2H),7.17(t,J＝12.0Hz,1H),6.98(d,J =8.7Hz,2H),6.71(d,J=2.3Hz,1H),6.63-6.57(m,1H),6.21(s,1H),5.96(d,J=3.0Hz,1H),5.75(dd , J=18.0, 8.7Hz, 1H), 5.05–4.99 (m, 1H), 4.90–4.82 (m, 1H), 4.70–4.61 (m, 2H), 4.15–4.12 (m, 1H), 3.87–3.81 (m, 6H), 2.73–2.63 (m, 3H), 2.40 (s, 3H), 2.33 (q, J=8.6Hz, 1H), 2.17 (dd, J=23.0, 11.0Hz, 1H), 2.11– 2.01 (m, 1H), 1.95–1.82 (m, 4H), 1.81–1.77 (m, 1H), 1.68 (dd, J=8.3, 3.9Hz, 1H), 1.49–1.43 (m, 3H), 1.28 ( d, J = 6.2 Hz, 3H), 0.90-0.77 (m, 3H) ppm.

Example 100

Step 1: Synthesis of Compound 100-1

Compound 100-0 (2.2 g, 10 mmol) and compound 1-1 (1.66 g, 10.9 mmol) were added to a mixed solvent of 20 mL of toluene, 20 mL of absolute ethanol and 10 mL of water, and then the catalyst tetrakis(triphenylphosphine) was added. Palladium (0.33g). Under nitrogen, the reaction mixture was warmed to 100°C and stirred overnight. After the completion of the reaction, the organic solvent was evaporated from the reaction mixture under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a yellow solid compound 100-1 (2.1 g, Yield: 85%).

MS(ESI, pos.ion) m/z: 248.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 100-2

Compound 100-1 (1.4 g, 5.9 mmol) and compound 1-2 (0.95, 5.6 mmol) were added to 30 mL of DMF solution, and K ₂ CO ₃ (1.2 g, 8.4 mmol) was added thereto under stirring at room temperature. The reaction mixture was warmed to 75°C under nitrogen protection for overnight reaction. After the completion of the reaction, the organic solvent was evaporated under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain compound 100-2 (1.6 g, yield) as a pale yellow solid. rate: 70%).

MS (ESI, pos.ion) m/z: 397.8 [M+H] ⁺ .

Step 3: Synthesis of Compound 100-3

Compound 100-2 (1.4 g, 3.5 mmol) was added to 35 mL of AcOH solution, and reduced iron powder (0.79 g, 14 mmol) was added at room temperature. The reaction mixture was heated at 105° C. and reacted overnight under nitrogen protection. After the reaction, the reaction solution was poured into 200 mL of water, a large amount of solid was precipitated, filtered, and the obtained solid was washed with water, and then placed under vacuum to dry to obtain a white solid compound 100-3 (1.0 g, yield: 85%). MS (ESI, pos.ion) m/z: 336.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 100-4

Compound 100-3 (1 g, 2.982 mmol) was added to 20 mL of toluene, under nitrogen protection and room temperature, phosphorus oxychloride (0.554 mL, 5.965 mmol) and N,N-dimethylaniline (0.15 mL, 1.193 mmol) were slowly injected mmol). After the addition was complete, the reaction mixture was warmed to 115°C and stirred overnight. After the reaction was completed, the reaction mixture was cooled to -6°C and stirred for 10 minutes, then the reaction was quenched with 2 ml of water, 20 ml of toluene was added, and the mixture was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown solid compound 100-4 (1.0 g, yield: 95%), which was directly carried out to the next reaction without further purification.

Step 5: Synthesis of Compound 100-5

Compound 100-4 (1.055 g, 3 mmol) and compound 1-3 (0.5 g, 0.9 mmol) were added to 15 mL of anhydrous DMF, then t-BuOK (0.3 g, 3 mmol) was added, and the reaction mixture was cooled under nitrogen protection The reaction was carried out at 40°C for 1 hour. After the reaction was completed, the reaction was quenched with 10 mL of water, then extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) , a white solid 100-5 was obtained (0.2 g, 30% yield).

Step 6: Synthesis of Compound 100-6

Compound 100-5 (0.2 g, 0.2 mmol) was dissolved in 10 mL of a 30% concentration of hydrochloric acid in ethyl acetate, and the reaction mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the obtained solid was washed once with 10 mL of ethyl acetate to obtain a white solid compound 100-6 (0.19 g, yield 100%), which was directly subjected to the next reaction without further purification.

MS (ESI, neg.ion) m/z: 784.3 [MH] ^- .

Step 7: Synthesis of Compound 100-7

Compound 100-6 (0.2 g, 0.2 mmol), compound 5-methylisoxazole-3-carboxylic acid (0.03 g, 0.3 mmol), EDCI (0.05 g, 0.3 mmol) and HOAT (0.04 g, 0.3 mmol) were combined It was added to a round-bottomed flask, and under nitrogen protection, 10 mL of dichloromethane was added, then cooled to 0°C, and then DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 5 mL of water, and extracted with ethyl acetate (10 mL×2). The organic phases were combined. The organic phases were washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. , the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain pale yellow solid 100-7 (90 mg, yield 40%).

MS(ESI,neg.ion)m/z:893.3[MH] ^- ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.38(s, 1H), 7.91(d, J=6Hz, 1H), 7.63(s, 1H), 7.54-7.53(m, 2H), 7.46(d, J=3Hz, 1H), 7.35-7.33(m,1H), 7.30(s,1H), 7.25-7.20(m,2H), 7.01-6.97(m,1H), 6.20(s,1H), 5.97- 5.96 (m, 1H), 5.78–5.74 (m, 1H), 5.02–4.99 (m, 1H), 4.84–4.81 (m, 1H), 4.70–4.66 (m, 2H), 4.16–4.10 (m, 1H) ), 3.86(s, 3H), 2.95–2.91(m, 1H), 2.70–2.68(m, 2H), 2.42(s, 3H), 2.35–2.31(m, 1H), 2.18–2.11(m, 1H ), 1.92–1.86 (m, 2H), 1.72–1.67 (m, 4H), 1.53–1.41 (m, 5H), 1.37–1.27 (m, 4H), 1.18–0.84 (m, 3H) ppm.

HPLC purity: 97.57%.

Example 101

synthetic route

Step 1: Synthesis of Compound 101-3

Compound 101-1 (50 mg, 0.29 mmol) and compound 101-2 (50 mg, 0.35 mmol) were dissolved in DMF (20 mL), then K ₂ CO ₃ (60 mg, 0.44 mmol) was added, and the reaction mixture was warmed to 110 ° C for reaction overnight. After the reaction, 10 mL of water was added to quench, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic phase was removed under reduced pressure. solvent to obtain compound 101-3 as an orange oily liquid, which was directly carried out to the next step without further purification.

MS (ESI, pos.ion) m/z: 292.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 101-4

Compound 121-3 (1 g, 3.4 mmol) obtained in the previous reaction was dissolved in glacial acetic acid (50 mL), iron powder (0.96 g, 17.2 mmol) was added, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and then the filtrate was poured into 1N hydrochloric acid (100 mL), a white solid was precipitated, filtered, the filter cake was washed with water, and dried in vacuo to obtain a yellow solid compound 101-4 (475 mg, two steps yield 61%).

MS (ESI, pos.ion) m/z: 230.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 101-5

Compound 101-4 (50 mg, 0.22 mmol) was added to toluene (20 mL), POCl ₃ (100 mg, 0.66 mmol) and N,N-dimethylaniline (13 mg, 0.11 mmol) were slowly added under stirring at room temperature, and the addition was complete. After that, the reaction solution was heated and refluxed for 5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether) to obtain compound 101-5 (35 mg, yield 64%) as a pale yellow solid after purification.

MS(ESI, pos.ion) m/z: 248.1 [M+H] ⁺ .

Step 4: Synthesis of Intermediate 101-6

Compound N-Boc-4-(R)-hydroxyproline (60 mg, 0.24 mmol) was dissolved in DMF (10 mL), NaH (60% dispersed in mineral oil, 25 mg, 0.6 mmol) was added under ice bath, After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. Compound 101-5 (60 mg, 0.24 mmol) was dissolved in DMF (1 mL), added to the above reaction solution, and stirring was continued for 4 hours. After the reaction, the reaction solution was poured into 50 mL of water, adjusted to pH 2-3 with 1N HCl, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed once with saturated sodium chloride solution, It was dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain a pale yellow solid compound 101-6 ( 85 mg, 80% yield).

MS (ESI, pos.ion) m/z: 443.1 [M+H] ⁺ .

Step 5: Synthesis of 101-7

Compound 101-6 (50 mg, 0.11 mmol), compound 1-9 (45 mg, 0.11 mmol), EDCI (24 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added to _{CH2Cl2 (} 15 mL) under nitrogen For protection, DIPEA (48 mg, 0.37 mmol) was added under ice bath. After the addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction, adjust the pH value to about 2 with 1N hydrochloric acid, then extract with dichloromethane (10 mL×3), combine the organic phases, wash the organic phases with saturated sodium chloride solution once, dry with anhydrous sodium sulfate, filter, reduce The organic solvent was spun dry, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 101-7 as a pale yellow solid (65 mg, yield 90%).

MS (ESI, pos.ion) m/z: 655.2 [M+H] ⁺ .

Step 6: Synthesis of Compounds 101-10

Compound 101-7 (135 mg, 0.23 mmol) was dissolved in 5N HCl in ethyl acetate (10 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, and the resulting solid was washed with 10 mL of ethyl acetate and then dried in vacuo.

The compound obtained after drying, compound 101-9 (116 mg, 0.25 mmol), EDCI (52 mg, 0.27 mmol) and HOAT (37 mg, 0.27 mmol) were added to dichloromethane (10 mL), and DIPEA ( 90 mg, 0.68 mmol), then the reaction mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=12:1) to obtain a pale yellow solid compound 101-10 (94 mg, two steps) Yield 50%) ppm.

MS (ESI, pos.ion) m/z: 820.4 [M+H] ⁺ .

Step 6: Synthesis of Compounds 101-11

Compound 101-10 (100 mg, 0.12 mmol) was dissolved in 1,2-dichloroethane (300 mL), Grubbs II catalyst (20 mg) was added under nitrogen protection, then the reaction mixture was warmed to 75°C and reacted for 48 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, and the obtained crude product was purified by preparative HPLC to obtain 101-11 as a white solid (69 mg, yield 73%).

MS(ESI, pos.ion) m/z: 792.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ) δ 10.42 (d, J=113.0 Hz, 1H), 7.57 (dd, J=33.2, 26.0 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.16 (dd, J=15.1, 7.4Hz, 3H), 6.95–6.83 (m, 2H), 5.92 (d, J=20.4Hz, 1H), 5.73 (dd, J=17.2, 8.5Hz, 1H), 5.35 ( d, J=4.5Hz, 1H), 4.98 (dd, J=31.8, 22.1Hz, 2H), 4.62 (t, J=7.5Hz, 1H), 4.54–4.32 (m, 2H), 4.05 (d, J =7.9Hz,1H),2.92(s,1H),2.62(dd,J=34.2,25.7Hz,3H),2.39–2.24(m,1H),2.00–1.73(m,6H),1.72–1.55( m, 6H), 1.54–1.43 (m, 6H), 1.18–1.08 (m, 2H), 1.00–0.78 (m, 4H) ppm.

Example 102

synthetic route

Step 1: Synthesis of Compound 102-2

Compound 102-0 (3.3 g, 15 mmol), compound 102-1 (2.3 g, 15 mmol), Pd(PPh ₃ ) ₄ (0.6 g, 0.5 mmol) and K ₂ CO ₃ (10 g, 75 mmol) were dissolved in THF ( 150 mL) and water (15 mL), the reaction mixture was stirred at room temperature overnight. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×100 mL), and the organic phases were combined. The organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered, and then the organic solvent was evaporated under reduced pressure to obtain a yellow solid compound 102-2 (3.1 g, yield: 84%).

Step 2: Synthesis of Compound 102-4

Compound 102-2 (1.0 g, 4.0 mmol) and compound 102-3 (0.9 g, 5 mmol) were dissolved in 20 mL of DMF, and K ₂ CO ₃ (1.1 g, 8 mmol) was added thereto. After addition, the reaction mixture was Reflux overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (100 mL×2), washed with 50 mL of saturated brine once, dried with anhydrous Na ₂ SO ₄ , and filtered, The organic solvent was then removed under reduced pressure to obtain a yellow solid 102-4 (1.5 g, yield: 91%), which was directly carried out to the next step without further purification.

Step 3: Synthesis of Compound 102-5

Compound 102-4 (1.7 g, 4.2 mmol) was dissolved in 30 mL of glacial acetic acid, then reduced iron powder (1.2 g, 21 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, the solid was removed by filtration, 50 ml of 1N HCl aqueous solution was added dropwise to the filtrate, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain the target compound 102-5 (1.2 g , Yield: 83%); directly proceed to the next step without further purification.

MS (ESI, pos.ion) m/z: 348 [M+H] ⁺ .

Step 4: Synthesis of Compound 102-6

Compound 102-5 (0.5 g, 1.4 mmol) was added to 15 mL of toluene, under nitrogen protection, phosphorus oxychloride (0.5 g, 3 mmol) was added, and then N,N-dimethylaniline (0.08 g, 0.6 mmol) was added slowly mmol), the reaction mixture was warmed to 110 °C and reacted for 6 hours. After the reaction was completed, the reaction system was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 102-6 (0.32 g, yield: 61%).

Step 5: Synthesis of Compound 102-7

Compound 102-6 (0.26 g, 0.7 mmol) was dissolved in DMF (20 mL), then compound 96-7 (0.2 g, 0.4 mmol) and potassium tert-butoxide (0.08 g, 0.7 mmol) were added, and the reaction mixture was at room temperature under stirring for 4 hours. After the reaction, the pH value was adjusted to 2-3 with 1N HCl aqueous solution, 50 mL of water was added, and the aqueous phase was extracted with ethyl acetate (20 mL×3), and then the organic phases were combined. The combined organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered, and then the organic phase was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V :V)=1:1) and purified to obtain compound 102-7 as a pale yellow solid (0.19 g, yield 60%).

MS (ESI, pos.ion) m/z: 898 [M+H] ⁺ .

Step 6: Synthesis of Compounds 102-10

Compound 102-7 (0.13 g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 30% hydrochloric acid in ethyl acetate (20 mL) was added, and the reaction mixture was stirred at room temperature for 2 Hours. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed once with 20 mL of ethyl acetate, and then dried in vacuo.

The dried solid obtained above, compound 102-9 (0.03 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 ml was added Dichloromethane was then cooled to 0°C and DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2: 1) Purification to obtain white solid compound 102-10 (0.13 g, 85% yield).

MS(ESI, pos.ion) m/z: 907.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ) δ 10.37 (s, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.63 (s, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.41 (d, J=2.2Hz, 1H), 7.37 (d, J=8.7Hz, 1H), 7.29–7.26 (m, 1H), 7.15 (d, J=8.3Hz, 1H), 6.95 (d, J= 8.7Hz, 2H), 6.69 (d, J=2.4Hz, 1H), 6.58 (dd, J=8.7, 2.4Hz, 1H), 6.20 (s, 1H), 5.94 (d, J=3.5Hz, 1H) ,5.73(dd,J=18.0,8.8Hz,1H),5.02-4.94(m,1H),4.87-4.79(m,1H),4.64(t,J=7.9Hz,1H),4.57(d,J = 11.5Hz, 1H), 4.10 (dd, J = 11.5, 4.2Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 2.93–2.88 (m, 1H), 2.67–2.63 (m, 2H), 2.39(s, 3H), 2.31(q, J=8.6Hz, 1H), 2.17–2.07 (m, 1H), 1.89–1.82 (m, 2H), 1.52–1.39 (m, 6H), 1.17 -1.04(m,3H),0.89-0.82(m,4H)ppm.

Example 103

synthetic route

Synthesis of Compound 103-2

Compound 2-13 (0.22 g, 0.29 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 30% hydrochloric acid in ethyl acetate (20 mL) was added, and the reaction mixture was stirred at room temperature for 2 Hours. After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed with 20 mL of ethyl acetate, and then dried in vacuo.

The above dried solid, compound 103-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 ml was added Dichloromethane was then cooled to 0°C and DIPEA (0.1 mL, 0.6 mmol) was added. After dripping. The reaction mixture was warmed to 30°C and reacted for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the organic solvent was removed under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification gave compound 103-2 as a white solid (0.05 g, 22% yield).

Example 104

synthetic route

Step 1: Synthesis of Compound 104-2

Compound 104-0 (2 g, 10.04 mmol) and compound 104-1 (2 g, 11.75 mmol) were dissolved in 40 mL of DMF, and K ₂ CO ₃ (4 g, 28.64 mmol) was added thereto. After the addition, the reaction mixture was warmed to React at 90°C overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 40 mL of EtOAc, the resulting mixture was washed with H ₂ O (40 mL×2), the organic phase was washed once with 50 mL of saturated brine, and then dried with anhydrous Na ₂ SO ₄ , then Filtration and concentration under reduced pressure gave yellow solid compound 104-2 (3.3 g, yield: 94%). MS (ESI, pos.ion) m/z: 349.9 [M+H] ⁺ .

Step 2: Synthesis of Compound 104-3

Compound 104-2 (3.3 g, 9.4 mmol) was dissolved in 40 mL of glacial acetic acid, then reduced iron powder (4.0 g, 71 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, and then filtered. 1N HCl solution was added dropwise to the obtained filtrate, and a large amount of white solid was precipitated, which was filtered again, and the obtained white solid was dried under vacuum to obtain compound 104-3 (2.7 g, yield: 99%); proceed directly to the next step without further purification reaction.

MS (ESI, pos.ion) m/z: 288.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 104-4

Compound 104-3 (1 g, 3.48 mmol) was added to 20 mL of toluene, phosphorus oxychloride (1 mL, 10.62 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added ). After the addition was completed, the reaction mixture was warmed to 110°C and reacted for 6 hours. After the reaction was completed, the reaction system was cooled to 0° C., and then the organic solvent was removed under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain a pale yellow solid Compound 104-4 (0.89 g, 83.4%).

Step 4: Synthesis of Compound 104-6

Potassium tert-butoxide (0.10 g, 0.9 mmol), compound 104-4 (0.20 g, 0.65 mmol) and compound 104-5 (0.2 g, 0.4 mmol) were added to 20 mL of anhydrous DMF, and the reaction mixture was warmed to 40 °C and stirred for 4 hours. After the reaction was complete, the reaction was quenched with 20 mL of water and washed once with 20 mL of ethyl acetate. The aqueous phase was adjusted to pH 4 with 1N hydrochloric acid solution, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were then washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered , and the organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a white solid compound 104-6 (0.24 g, yield: 43.71%).

MS (ESI, pos.ion) m/z: 838.3 [M+H] ⁺ .

Step 5: Synthesis of target compound 104-7

Compound 104-6 (0.15 g, 0.19 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, and then a 30% concentration of hydrochloric acid in ethyl acetate (2 mL) was added, and the reaction mixture was reacted at room temperature for 4 Hour. After the reaction was completed, the reaction mixture was filtered, and the resulting white solid was washed once with 20 mL of ethyl acetate, and then dried in vacuo.

The solid obtained from the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.05g, 0.4mmol), EDCI (0.13g, 2.8mmol) and HOAT (0.1g, 3.0mmol) were added to a round bottom flask, Under nitrogen, 20 mL of dichloromethane was added, then cooled to 0°C, and then DIPEA (0.5 mL, 10 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with dichloromethane (20 mL×2), and then the organic phases were combined. The organic phase was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V) =2:1) purification to give white solid compound 104-7 (0.132 g, 80% yield).

MS(ESI, pos.ion) m/z: 847.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.45 (s, 1H), 8.23 (d, J=7.3 Hz, 1H), 8.03 (s, 1H), 7.17 (dd, J=8.5, 2.9 Hz, 1H ),7.09–7.01(m,3H),6.78(d,J=2.9Hz,1H),6.66(dd,J=8.8,2.9Hz,1H),6.35–6.15(m,2H),5.95(s, 1H), 5.76(dd, J=17.5, 9.2Hz, 1H), 5.02-4.98(m, 1H), 4.83-4.77(m, 2H), 4.65(t, J=8.1Hz, 1H), 4.52(dt , J=12.1, 6.0Hz, 1H), 4.06 (dd, J=11.5, 3.7Hz, 1H), 2.97–2.88 (m, 1H), 2.75–2.63 (m, 3H), 2.24 (dd, J=22.5 ,11.1Hz,1H),1.84(dd,J=7.8,6.1Hz,3H),1.69–1.64(m,1H),1.48(dddd,J=38.1,32.1,15.6,8.3Hz,8H),1.33( dd, J=5.9, 1.1 Hz, 6H), 1.20–1.04 (m, 3H), 0.98–0.86 (m, 2H) ppm.

HPLC purity: 90.46%.

Example 105

synthetic route

Step 1: Synthesis of Compound 105-2

Compound 105-0 (2 g, 10.04 mmol) and compound 105-1 (2 g, 10.97 mmol) were dissolved in 40 mL of DMF, and K ₂ CO ₃ (4 g, 28.64 mmol) was added thereto. After the addition was complete, the reaction mixture was warmed to 90°C for overnight reaction. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 40 mL of EtOAc, washed twice with 40 mL of H ₂ O, and once with 50 mL of saturated brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , then filtered, and the organic solvent was removed under reduced pressure to obtain yellow solid compound 105-2 (3 g, yield: 82.69%). MS (ESI, pos.ion) m/z: 361.9 [M+H] ⁺ .

Step 2: Synthesis of Compound 105-3

Compound 105-2 (3 g, 8.3 mmol) was dissolved in 60 mL of glacial acetic acid, then reduced iron powder (4.0 g, 71 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, the solid was removed by filtration, 100 ml of 1N HCl solution was added dropwise to the obtained filtrate, a large amount of white solid was precipitated, and then filtered, and the obtained white solid was dried under vacuum to obtain compound 105-3( 2g, yield: 80.6%); the next reaction was carried out directly without further purification.

MS (ESI, pos.ion) m/z: 300.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 105-4

Compound 105-3 (0.5 g, 1.67 mmol) was added to 20 mL of toluene, phosphorus oxychloride (1 mL, 10.62 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was added slowly mmol). After the addition was completed, the reaction mixture was warmed to 110°C and reacted for 6 hours. After the reaction was completed, the reaction system was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid Compound 105-4 (0.33 g, 60%).

Step 4: Synthesis of Compound 105-6

Potassium tert-butoxide (0.10 g, 0.9 mmol), compound 105-4 (0.24 g, 0.75 mmol) and compound 105-5 (0.2 g, 0.4 mmol) were added to 20 mL of dry DMF. After the addition was complete, the reaction mixture was warmed to 40°C and stirred for 4 hours. After the reaction was complete, the reaction was quenched with 20 mL of water, and the resulting mixture was washed once with 20 mL of ethyl acetate. The pH value of the aqueous phase was adjusted to about 4 with 1N hydrochloric acid solution, then extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and The organic solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain white solid compound 105-6 (0.33 g, yield: 54.56%) )

MS (ESI, pos.ion) m/z: 851.0 [M+H] ⁺ .

Step 5: Synthesis of Compound 105-7

Compound 105-6 (0.3 g, 0.35 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 2 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 2 hours . After the reaction was completed, the reaction mixture was filtered, and the obtained white solid was washed once with 20 mL of ethyl acetate, and then dried in vacuo.

The above dried solid, 5-methylisoxazole-3-carboxylic acid (0.05 g, 0.4 mmol), EDCI (0.13 g, 2.8 mmol) and HOAT (0.1 g, 3.0 mmol) were added to a round bottom flask, 20 mL of dichloromethane was added under nitrogen, then cooled to 0°C, and then DIPEA (0.5 mL, 10 mmol) was added. After the dropwise addition was complete, the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, and then extracted with 20 mL of dichloromethane (20 mL×2), and then the organic phases were combined. The organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification gave compound 105-7 as a white solid (0.261 g, 80% yield).

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.34 (d, J=70.3 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.02 (d, J=8.8Hz, 1H), 6.76 (d, J=3.0Hz, 1H), 6.67–6.63 (m, 2H), 6.58 (dd, J=8.7, 2.5Hz, 1H) ), 6.22(s, 1H), 5.93(d, J=3.4Hz, 1H), 5.75(dd, J=18.2, 8.7Hz, 1H), 5.02–4.98(m, 1H), 4.87–4.82(m, 1H), 4.65(t, J＝7.9Hz, 1H), 4.58-4.50(m, 2H), 4.15-4.10(m, 1H), 3.80(s, 3H), 2.96-2.88(m, 1H), 2.68 –2.61(m,3H),2.32(q,J=8.7Hz,1H),2.17–2.11(m,1H),2.07(d,J=7.8Hz,1H),1.88(ddd,J=14.0,12.8 ,9.5Hz,3H),1.72–1.67(m,1H),1.54–1.43(m,6H),1.33(d,J=6.1Hz,6H),1.20–1.02(m,3H),0.94–0.84( m,2H)ppm.

HPLC purity: 92.89%.

Example 106

synthetic route

Synthesis of Compound 106-1

Compound 96-8 (0.21 g, 0.26 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., and then 2 mL of 30% concentration of hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 2 hours . After completion of the reaction, the reaction mixture was filtered, the obtained white solid was washed once with 20 ml of ethyl acetate, and then the obtained solid was dried under vacuum.

The above dried solid, compound 1-methylpyrazole-3-carboxylic acid (0.05g, 0.4mmol), EDCI (0.13g, 2.8mmol) and HOAT (0.1g, 3.0mmol) were added to a round bottom flask, 20 mL of dichloromethane was added under nitrogen protection, then cooled to 0°C, and then DIPEA (0.5 mL, 10 mmol) was added slowly. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was complete, the reaction was quenched with 10 mL of water, taken twice with 20 mL of dichloromethane, and the organic phases were combined. The organic phase was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the liquid was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification to obtain white solid compound 106-1 (0.203 g, 88.6% yield).

¹ H NMR (600 MHz, CDCl ₃ ): δ 7.68 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.36(t,J＝7.3Hz,1H),7.31(s,1H),7.17-7.13(m,2H),6.98(d,J＝8.4Hz,2H),6.64(d,J＝8.5Hz,1H) ), 6.00(s, 1H), 5.74(dd, J=17.5, 8.6Hz, 1H), 5.07–4.92(m, 2H), 4.71(s, 1H), 4.57(t, J=7.2Hz, 1H) ,4.44(d,J＝10.8Hz,1H),4.18(dd,J＝11.0,4.7Hz,1H),3.87(d,J＝5.4Hz,6H),3.51(q,J＝7.1Hz,2H) ,2.94–2.90(m,1H),2.62–2.50(m,3H),2.38(s,2H),2.31(d,J=8.6Hz,1H),2.08–1.89(m,7H),1.18–1.09 (m, 4H), 0.92 (d, J=4.5Hz, 2H) ppm.

HPLC purity: 91.73%.

Example 107

synthetic route

Step 1: Synthesis of Compound 107-2

Compound 107-0 (0.96 g, 4.1 mmol) and compound 107-1 (1 g, 6.5 mmol) were dissolved in 20 mL of DMF, and K ₂ CO ₃ (2 g, 14.32 mmol) was added thereto. After the addition was complete, the reaction mixture was The temperature was raised to 90°C for overnight reaction. After the reaction was completed, the reaction system was cooled to room temperature, diluted with 20 mL of EtOAc, washed twice with 20 mL of H ₂ O, and once with 10 mL of saturated brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered again, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 107-2 (1.5 g, yield: 100%). Step 2: Synthesis of Compound 107-3

Compound 107-2 (1.5 g, 4.1 mmol) was dissolved in 30 mL of glacial acetic acid, then reduced iron powder (2 g, 35 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature, then the solid was removed by filtration, 50 ml of 1N HCl solution was added dropwise to the obtained filtrate, and a large amount of white solid was precipitated, which was filtered again, and the obtained white solid was dried under vacuum to obtain the target compound 107- 3 (1 g, yield: 80%); proceeded to the next step without further purification.

MS (ESI, pos.ion) m/z: 306.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 107-4

Compound 107-3 (0.5 g, 2 mmol) was added to 20 mL of toluene, phosphorus oxychloride (1 mL, 10.62 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.2 mL, 1.4 mmol) was slowly added . The reaction mixture was warmed to 110°C and stirred for 6 hours. After the reaction was completed, the reaction system was cooled to 0° C., and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain pale yellow Solid compound 107-4 (0.29 g, 50.00%).

MS(ESI, pos.ion) m/z: 324.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 107-6

At room temperature, potassium tert-butoxide (0.10 g, 0.9 mmol), compound 107-4 (0.28 g, 0.86 mmol) and compound 107-5 (0.2 g, 0.4 mmol) were added to 20 mL of anhydrous DMF, the reaction mixture was The temperature was raised to 40°C and stirred for 4 hours. After the reaction was complete, the reaction was quenched with 20 mL of water and washed once with 20 mL of ethyl acetate. The separated aqueous phase was adjusted to pH around 4 with 1N hydrochloric acid solution, then extracted with ethyl acetate (20 mL×3), and then the organic phases were combined. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) Purified to give white solid compound 107-6 (0.165 g, yield: 50%)

MS (ESI, pos.ion) m/z: 856.3 [M+H] ⁺ .

Step 5: Synthesis of Compound 107-7

Compound 107-6 (0.165 g, 0.193 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0 °C, then 30% hydrochloric acid in ethyl acetate (2 mL) was added, and the reaction mixture was stirred at room temperature for 4 Hour. After the reaction was complete, the reaction mixture was filtered, and the resulting white solid was washed once with 10 mL of ethyl acetate, and then dried in vacuo.

The dried above solid, compound 5-methylisoxazole-3-carboxylic acid (0.05g, 0.4mmol), EDCI (0.13g, 2.8mmol), HOAT (0.1g, 3.0mmol) were added to a round bottom flask , under nitrogen protection, 20 mL of dichloromethane was added, then cooled to 0 °C, and then DIPEA (0.5 mL, 10 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, and then extracted with dichloromethane (20 mL×2), and then the organic phases were combined. The organic phase was washed once with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2 : 1) Purification to obtain white solid compound 107-7 (0.1189 g, yield 71%).

MS(ESI, pos.ion) m/z: 865.3[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.45 (s, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.91 (s, 1H), 7.57-7.54 (m, 2H), 7.48-7.45 (m, 2H), 7.43–7.40 (m, 1H), 7.31–7.29 (m, 1H), 7.23–7.21 (m, 1H), 7.19 (d, J=8.1Hz, 1H), 7.12 (t, J ＝8.7Hz, 2H), 7.05(t, J＝7.6Hz, 1H), 6.16(s, 1H), 5.97(d, J＝3.3Hz, 1H), 5.75(dd, J＝17.9, 8.8Hz, 1H) ), 5.02–4.98 (m, 1H), 4.88–4.83 (m, 1H), 4.69 (dd, J=13.9, 6.0Hz, 2H), 4.13 (dd, J=11.5, 4.2Hz, 1H), 2.95– 2.90 (m, 1H), 2.70–2.65 (m, 3H), 2.38 (s, 3H), 2.33 (dd, J=17.1, 8.6Hz, 1H), 2.19 (dd, J=23.4, 11.1Hz, 1H) ,1.89–1.84(m,2H),1.68(dd,J=16.1,7.2Hz,1H),1.49(qdd,J=11.0,8.0,3.3Hz,6H),1.19–1.04(m,3H),0.97 -0.85(m,3H)ppm.

HPLC purity: 91.55%.

Example 108

synthetic route

Synthesis of Compound 108-1

Compound 100-6 (0.1 g, 0.1 mmol), compound 1-4 (0.02 g, 0.1 mmol), EDCI (0.03 g, 0.1 mmol) and HOAT (0.02 g, 0.1 mmol) were added to a round bottom flask under nitrogen 10 mL of dichloromethane was added under protection, then cooled to 0°C, and then DIPEA (0.05 mL, 0.3 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 5 mL of water, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic phases were washed twice with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and removed under reduced pressure Organic solvent, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain purified pale yellow solid compound 108-1 (40 mg, yield 40%).

MS(ESI,neg,ion)m/z:892.2[MH] ^- ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.39 (s, 1H), 7.53 (d, J=6.0 Hz, 2H), 7.44 (s, 1H), 7.39 (d, J=3.0 Hz, 1H) ,7.32(s,3H),7.20–7.18(m,1H),7.07(s,1H),6.98(d,J=12.0Hz,2H),6.64(s,1H),6.01(s,1H), 5.80-5.70(m, 1H), 5.04-5.01(m, 1H), 4.71(s, 1H), 4.61-4.53(m, 1H), 4.50(d, J=12.0Hz, 1H), 4.17-4.15( m,1H), 3.95(s,1H), 3.88(s,3H), 3.86(s,3H), 2.92(s,1H), 2.62–2.53(m,1H), 2.35–2.29(m,1H) ,2.05-2.01(m,1H),1.93(s,1H),1.82-1.74(m,1H),1.64(s,3H),1.51(s,1H),1.28(s,3H),1.16-1.09 (m, 2H), 0.93–0.88 (m, 3H) ppm. HPLC purity: 92.40%.

Example 109

synthetic route

Step 1: Synthesis of Compound 109-3

Compound 109-1 (0.69 g, 4.0 mmol) and compound 109-2 (1 g, 4.0 mmol) were dissolved in 20 mL of DMF solution, and K ₂ CO ₃ (1.0 g, 7.3 mmol) was added thereto. The reaction mixture was warmed to 110°C for overnight reaction. After the reaction was completed, 10 mL of water was added to quench the reaction, then extracted with ethyl acetate (20 mL×3), the organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. The crude product of compound 109-3 as an orange oily liquid was obtained by concentration, and the next step reaction was carried out directly without purification.

Step 2: Synthesis of Compound 109-4

The crude product of compound 109-3 (1.6 g, 4 mmol) obtained in the previous reaction was dissolved in 50 mL of glacial acetic acid, then iron powder (1.1 g, 20 mmol) was added, and the reaction mixture was heated to 110° C. for 8 hours. After the reaction was completed, the reaction system was cooled to room temperature, and then filtered. The filtrate was concentrated and poured into 1N 100 mL hydrochloric acid solution, a solid was precipitated, and then filtered, the filter cake was washed with water, and dried in vacuo to obtain yellow solid compound 109-4 (990 mg, two-step yield 74%).

Step 3: Synthesis of Compound 109-5

Compound 109-4 (1 g, 3.1 mmol) was dissolved in 100 mL of toluene solution, POCl 3 (939 mg, 6.1 mmol) and N,N-dimethylaniline (185 mg, 1.5 mmol) were slowly added with stirring at room temperature. After the addition was complete, the reaction mixture was refluxed for 5 hours. After the completion of the reaction, the reaction system was cooled to room temperature, then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent is petroleum ether) to obtain compound 109-5 (0.8 g, yield 80%) as a pale yellow solid ).

Step 4: Synthesis of Compound 109-7

Compound 107-5 (150 mg, 0.26 mmol) was dissolved in 50 mL of DMF solution, and compound 109-5 (140 mg, 0.39 mmol) and potassium tert-butoxide (88 mg, 0.79 mmol) were added thereto. The reaction mixture was stirred at room temperature for 4 hours. After the reaction, the pH value was adjusted to 2-3 with 1N HCl solution, then 50 mL of water was added to dilute, and the aqueous phase was extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1: 1) Purification to obtain light yellow solid compound 109-7 (0.18 g, yield 77%).

Step 5: Synthesis of Compound 109-8

Compound 109-7 (339 mg, 0.38 mmol) was dissolved in 5N HCl in ethyl acetate (30 mL), and the reaction solution was stirred at room temperature for 2 hours. After the completion of the reaction, the organic solvent was evaporated under reduced pressure to obtain a white solid compound 109-8 (0.29 g, yield 90%).

Step 6: Synthesis of Compound 109-9

Compound 109-8 (110 mg, 0.13 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ , compound 5-methylisoxazole-3-carboxylic acid (20 mg, 0.15 mmol), EDCI (32 mg, 0.17 mmol) and HOAT were added (22 mg, 0.17 mmol), and DIPEA (54 mg, 0.42 mmol) was added under ice bath. The reaction solution was then warmed to room temperature and stirred for 4 hours. After the reaction, the organic solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 109-9 (0.1 g, yield) as a pale yellow solid. rate 80%).

MS(ESI, pos.ion) m/z: 895.3 [M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 10.40 (s, 1H), 8.05 (d, J=6.7 Hz, 1H), 7.73 (s, 1H), 7.59-7.50 (m, 2H), 7.39 (dd , J=8.2, 2.0Hz, 1H), 7.36 (d, J=2.0Hz, 1H), 7.30 (d, J=8.1Hz, 1H), 7.23 (dd, J=8.6, 3.0Hz, 1H), 7.16 (dd, J=8.9, 4.6Hz, 1H), 7.11–7.07 (m, 1H), 7.02–6.96 (m, 2H), 6.24 (d, J=0.6Hz, 1H), 5.99 (s, 1H), 5.77(dd,J=17.2,9.5Hz,1H),5.08–4.97(m,1H),4.79(dd,J=11.2,7.1Hz,2H),4.66(t,J=8.1Hz,1H),4.09 (dd, J=11.5, 3.9Hz, 1H), 3.87(s, 3H), 2.99–2.88(m, 1H), 2.77–2.64(m, 3H), 2.39(s, 3H), 2.36(dd, J = 16.9, 8.5Hz, 1H), 2.28–2.15 (m, 1H), 1.94–1.79 (m, 2H), 1.56 (dd, J=9.5, 5.9Hz, 1H), 1.53–1.48 (m, 3H), 1.34 (dd, J=10.8, 6.7 Hz, 3H), 1.28 (s, 3H), 1.20–0.95 (m, 2H) ppm.

HPLC purity: 97.04%.

Example 110

synthetic route

Step 1: Synthesis of Compound 110-2

Compound 110-0 (3.3 g, 15 mmol), compound 110-1 (2.5 g, 15 mmol), Pd(PPh ₃ ) ₄ (0.6 g, 0.5 mmol) and K ₂ CO ₃ (10 g, 72 mmol) were added to THF ( 150 mL) and water (15 mL), the reaction mixture was stirred at room temperature overnight. After the reaction was completed, saturated sodium chloride solution (200 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3×100 mL), and then the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow solid compound 110-2 (3.3 g, yield: 83%).

Step 2: Synthesis of Compound 110-4

Compound 110-2 (1.0 g, 3.8 mmol) and compound 110-3 (0.8 g, 5 mmol) were dissolved in 20 mL of DMF, and K ₂ CO ₃ (1.0 g, 7.2 mmol) was added thereto. After the addition was complete, the reaction mixture was refluxed overnight. After the reaction was completed, the reaction system was cooled to room temperature, diluted with 100 mL of EtOAc, washed twice with 100 mL of H ₂ O, and then once with 50 mL of saturated brine. The separated organic phase was dried over anhydrous Na ₂ SO ₄ , and then concentrated under reduced pressure to obtain yellow solid compound 110-4 (1.5 g, yield: 96%), which was directly carried out to the next reaction without further purification.

Step 3: Synthesis of Compound 110-5

Compound 110-4 (1.5 g, 3.6 mmol) was dissolved in 30 mL of glacial acetic acid, then reduced iron powder (0.7 g, 10 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was complete, the reaction system was cooled to room temperature, then the solid was removed by filtration, 1N HCl solution was added dropwise to the obtained filtrate, a large amount of white solid was precipitated, and then filtered, and the obtained white solid was dried under vacuum to obtain the target compound 110-5( 1.2 g, yield: 94%), the next reaction was carried out directly without further purification.

MS(ESI,pos.ion)m/z:354.1[M+H] ⁺

Step 4: Synthesis of Compound 110-6

Compound 110-5 (0.5 g, 1.4 mmol) was added to 15 mL of toluene, phosphorus oxychloride (0.5 g, 3 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.08 g, 0.6 mmol) was added slowly mmol). The temperature of the reaction mixture was raised to 110°C, and the reaction was carried out for 6 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to 0°C, and then concentrated under reduced pressure. The obtained mixture was purified by silica gel column (petroleum ether:ethyl acetate (V:V)=5:1) to obtain compound 110 as a pale yellow solid. -6 (0.4 g, yield: 76%).

Step 5: Synthesis of Compound 110-7

Compound 110-6 (0.2 g, 0.54 mmol) was dissolved in DMF (20 mL), and thereto were added compound 107-5 (0.15 g, 0.26 mmol) and potassium tert-butoxide (0.06 g, 0.53 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was adjusted to pH 2-3 with 1N HCl, and then diluted with 50 mL of water, then the aqueous phase was extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution, then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 110-7 as a pale yellow solid (0.23 g, 96% yield).

MS (ESI, pos.ion) m/z: 904.3 [M+H] ⁺ .

Step 6: Synthesis of Compounds 110-10

Compound 110-7 (0.23 g, 0.25 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of a 30% hydrochloric acid/ethyl acetate solution was added. The reaction mixture was stirred at room temperature for 2 hours, then filtered, and the resulting white solid was rinsed with 20 mL of ethyl acetate.

The solid obtained from the above reaction, compound 110-9 (0.04 g, 0.31 mmol), EDCI (0.07 g, 0.36 mmol) and HOAT (0.05 g, 0.37 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 ml of dichloride were added Methane, then cooled to 0 °C, and DIPEA (0.15 mL, 0.86 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1 ) to give compound 110-10 as a white solid (0.15 g, 63% yield).

MS(ESI, pos.ion) m/z: 913.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ 10.41(s, 1H), 8.07(s, 1H), 7.88(s, 1H), 7.42(d, J=2.2Hz, 1H), 7.33-7.27(m, 3H), 7.23–7.20 (m, 1H), 7.18 (d, J=8.3Hz, 1H), 7.15–7.11 (m, 1H), 7.11–7.05 (m, 1H), 7.01 (t, J=8.8Hz) ,1H),6.22(s,1H),5.97(s,1H),5.74(dd,J=17.3,9.4Hz,1H),5.03–4.96(m,1H),4.83–4.73(m,2H), 4.64(t,J=8.1Hz,1H),4.07(dd,J=11.5,3.9Hz,1H),3.92(s,3H),2.94-2.86(m,1H),2.75-2.61(m,3H) ,2.37(s,3H),2.33(dd,J=17.2,8.7Hz,1H),2.20(d,J=8.6Hz,1H),1.87-1.79(m,2H),1.52-1.45(m,3H) ), 1.17–1.05 (m, 3H), 0.96–0.78 (m, 6H) ppm.

Example 111

synthetic route

Step 1: Synthesis of Compound 111-2

Compound 111-0 (3.3 g, 15 mmol), compound 111-1 (2.5 g, 15 mmol), Pd(PPh ₃ ) ₄ (0.6 g, 0.5 mmol) and K ₂ CO ₃ (10 g, 72 mmol) were suspended in THF ( 150 mL) and water (15 mL) in a mixed solvent. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, saturated sodium chloride solution (200 mL) was added to quench the reaction, followed by extraction with ethyl acetate (3×100 mL), and the organic phases were combined. The organic phase was washed once with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 111-2 (3.3 g, yield: 83%).

Step 2: Synthesis of Compound 111-4

Compound 111-2 (1.0 g, 3.8 mmol) and compound 111-3 (0.85 g, 4.7 mmol) were dissolved in 20 mL of DMF, and K ₂ CO ₃ (1.0 g, 7.2 mmol) was added thereto. After the addition was complete, the reaction mixture was refluxed overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 100 mL of EtOAc, rinsed with 100 mL of H ₂ O (10 mL×2), and once with 50 mL of saturated brine. The separated organic phase was dried with anhydrous Na ₂ SO ₄ , filtered again, and then the organic solvent was removed under reduced pressure to obtain a yellow solid compound 111-4 (1.5 g, yield: 93%), which was directly carried out to the next step without further purification. .

Step 3: Synthesis of Compound 111-5

Compound 111-4 (1.5 g, 3.5 mmol) was dissolved in 30 mL of glacial acetic acid, then reduced iron powder (0.7 g, 10 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered to remove the solid, 50 ml of 1N HCl solution was added dropwise to the obtained filtrate, and a large amount of white solid was precipitated, which was filtered again, and the obtained white solid was dried under vacuum to obtain compound 111-5 (1.3 g, yield: 100%), the next reaction was directly carried out without further purification.

MS(ESI,pos.ion)m/z:366[M+H] ⁺

Step 4: Synthesis of Compound 111-6

Compound 111-5 (0.5 g, 1.4 mmol) was added to 15 mL of toluene, phosphorus oxychloride (0.5 g, 3 mmol) was added under nitrogen protection, and then N,N-dimethylaniline (0.08 g, 0.6 mmol) was slowly added ), the reaction mixture was warmed to 110° C. and reacted for 6 hours. After the reaction was completed, the reaction mixture was cooled to 0°C, and then the organic solvent was removed under reduced pressure. The resulting mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid Compound 111-6 (0.12 g, yield: 23%).

Step 5: Synthesis of Compound 111-7

Compound 111-6 (0.12 g, 0.31 mmol) was dissolved in DMF (20 mL), and thereto were added compound 107-5 (0.12 g, 0.21 mmol) and potassium tert-butoxide (0.06 g, 0.53 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction, the pH value of the reaction mixture was adjusted to 2-3 with 1N HCl aqueous solution, 50 mL of water was added to dilute, and then extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1 ) was purified to obtain compound 111-7 as a pale yellow solid (0.1 g, yield 51%).

MS(ESI, pos.ion) m/z: 916[M+H] ⁺ .

Step 6: Synthesis of Compounds 111-10

Compound 111-7 (0.1 g, 0.11 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 2 hours , then filtered, and the resulting white solid was rinsed with 20 mL of ethyl acetate and dried in vacuo.

The solid obtained by drying above, compound 111-9 (0.02 g, 0.16 mmol), EDCI (0.03 g, 0.16 mmol) and HOAT (0.02 g, 0.15 mmol) were added to a round-bottomed flask, and 20 mL of dichloride was added under nitrogen protection Methane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×2), and the organic phases were combined. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1 ) was purified to give compound 111-10 as a white solid (77 mg, 83% yield).

MS(ESI, pos.ion) m/z: 925[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ )δ10.36(s,1H), 7.91(s,1H), 7.58(s,1H), 7.42-7.36(m,2H), 7.34-7.28(m,2H), 7.26–7.23(m,1H),7.16(d,J=8.3Hz,1H),7.00(t,J=8.8Hz,1H),6.69(d,J=2.4Hz,1H),6.59(dd,J =8.7,2.4Hz,1H),6.20(s,1H),5.94(d,J=3.3Hz,1H),5.74(d,J=9.4Hz,1H),5.02–4.94(m,1H),4.86 –4.79(m, 1H), 4.64(t, J=7.8Hz, 1H), 4.57(d, J=11.4Hz, 1H), 4.10(dd, J=11.4, 4.3Hz, 1H), 3.92(s, 3H), 3.80 (s, 3H), 2.97–2.85 (m, 1H), 2.70–2.57 (m, 3H), 2.39 (s, 3H), 2.35–2.27 (m, 1H), 2.12 (d, J= 11.7Hz, 1H), 1.93–1.83 (m, 2H), 1.50–1.45 (m, 3H), 1.18–1.04 (m, 3H), 0.95–0.80 (m, 6H) ppm.

Example 112

synthetic route

Synthesis of Compound 112-2

Compound 109-7 (0.21 g, 0.24 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0°C, and then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 2 hours , then filtered, and the resulting white solid was washed once with 20 mL of ethyl acetate and dried in vacuo.

The solid obtained by drying above, compound 112-1 (0.02g, 0.2mmol), EDCI (0.04g, 0.2mmol) and HOAT (0.03g, 0.2mmol) were added to a round-bottomed flask, and 20 mL of dichloride was added under nitrogen protection Methane, then cooled to 0 °C and DIPEA (0.1 mL, 0.6 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic phase was washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) purification gave compound 112-2 as a white solid (0.14 g, 64% yield).

MS(ESI, pos.ion) m/z: 894[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ 10.51 (s, 1H), 7.92 (s, 1H), 7.56-7.46 (m, 3H), 7.38 (d, J=2.1Hz, 1H), 7.29-7.26 ( m, 2H), 7.20–7.11 (m, 2H), 7.02–6.93 (m, 4H), 6.63 (d, J=2.1Hz, 1H), 6.04 (s, 1H), 5.76–5.64 (m, 1H) ,5.05–4.94(m,1H),4.60(t,J=7.7Hz,1H),4.54–4.40(m,2H),4.08(dd,J=11.2,4.2Hz,1H),3.86(s,3H) ), 3.83(s, 3H), 2.92–2.82(m, 1H), 2.70–2.57(m, 2H), 2.51–2.42(m, 1H), 2.30–2.21(m, 1H), 2.06–1.90(m , 2H), 1.88–1.71 (m, 4H), 1.56–1.47 (m, 4H), 1.12–1.04 (m, 2H), 0.90–0.82 (m, 3H) ppm.

Example 113

synthetic route

Step 1: Synthesis of Compound 113-2

Compound 113-0 (3.3 g, 15 mmol), 113-1 (2.3 g, 15 mmol), Pd(PPh ₃ ) ₄ (0.6 g, 0.5 mmol) and K ₂ CO ₃ (10 g, 75 mmol) were added to THF (150 mL) ) and water (15 mL), the reaction mixture was stirred overnight at room temperature under nitrogen protection. After the reaction, saturated sodium chloride solution (200 mL) was added to quench the reaction, then extracted with ethyl acetate (3×100 mL), and the organic phases were combined. The organic phase was washed with 40 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow solid compound 113-2 (3.1 g, yield: 84%).

Step 2: Synthesis of Compound 113-4

Compound 113-2 (0.8 g, 3.2 mmol) and compound 113-3 (0.75 g, 4 mmol) were dissolved in 20 mL of DMF, and K ₂ CO ₃ (0.9 g, 7 mmol) was added thereto. After the addition was complete, the reaction mixture was refluxed overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (100 mL×2), and washed with 50 mL of saturated brine once. The separated organic phase was dried over anhydrous Na ₂ SO ₄ , then filtered, and finally concentrated under reduced pressure to obtain yellow solid compound 113-4 (1.3 g, yield: 97%), which was directly carried out to the next reaction without further purification.

Step 3: Synthesis of Compound 113-5

Compound 113-4 (1.3 g, 3.1 mmol) was dissolved in 20 mL of glacial acetic acid, then reduced iron powder (0.8 g, 5 mmol) was added, and the reaction mixture was warmed to 115° C. and stirred for 3 hours. After the reaction was completed, cooled to room temperature, filtered and removed the solid, 50 ml of 1N HCl solution was added dropwise to the obtained filtrate, a large amount of white solid was precipitated, filtered, and the obtained white solid was dried under vacuum to obtain compound 113-5 (1.0 g, Yield: 90%).

MS(ESI, pos.ion) m/z: 352[M+H] ⁺ .

Step 4: Synthesis of Compound 113-6

Compound 113-5 (0.5 g, 1.4 mmol) was added to 15 mL of toluene, under nitrogen protection, phosphorus oxychloride (0.5 g, 3 mmol) was added, and then N,N-dimethylaniline (0.08 g, 0.6 mmol) was added slowly mmol). The temperature of the reaction mixture was raised to 110°C, and the reaction was carried out for 6 hours. After the reaction was completed, it was cooled to 0°C, and the organic solvent was removed under reduced pressure. The obtained mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=5:1) to obtain a pale yellow solid product 113-6 (0.35 g, yield: 66%).

Step 5: Synthesis of Compound 113-7

Compound 113-6 (0.2 g, 0.54 mmol) was dissolved in DMF (20 mL), and compound 107-5 (0.2 g, 0.35 mmol) and potassium tert-butoxide (0.08 g, 0.7 mmol) were added thereto, and the reaction mixture was Stir at room temperature for 4 hours. After the reaction, the pH value of the reaction mixture was adjusted to 2-3 with 1N HCl aqueous solution, and then 50 mL of water was added to dilute, and then extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting concentrate was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1 : 1) Purification to obtain light yellow solid 113-7 (0.25 g, yield 78%).

MS (ESI, pos.ion) m/z: 902.3 [M+H] ⁺ .

Step 6: Synthesis of Compound 113-10

Compound 113-7 (0.2 g, 0.2 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 20 mL of 30% concentration of hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 2 hours , then filtered, and the resulting white solid was rinsed with 20 mL of ethyl acetate and dried in vacuo.

The solid obtained after drying, compound 113-9 (0.03 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, and 20 mL was added under nitrogen protection. Dichloromethane was then cooled to 0°C and finally DIPEA (0.1 mL, 0.6 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was complete, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic phase was washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained concentrate was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2 : 1) Purification to obtain white solid compound 113-10 (0.17 g, yield 78%).

MS(ESI, pos.ion) m/z: 911.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ 10.43(s, 1H), 8.22(s, 1H), 7.95(s, 1H), 7.55-7.48(m, 2H), 7.45(d, J=2.3Hz, 1H), 7.33–7.29 (m, 2H), 7.28–7.26 (m, 1H), 7.17 (d, J=8.3Hz, 1H), 7.10 (d, J=8.6Hz, 1H), 7.00–6.89 (m , 2H), 6.07(s, 1H), 5.90(s, 1H), 5.80–5.69(m, 1H), 5.03–4.95(m, 1H), 4.88–4.76(m, 2H), 4.68(t, J = 8.1Hz, 1H), 4.07 (dd, J = 11.6, 3.8Hz, 1H), 3.84 (s, 3H), 2.94–2.87 (m, 1H), 2.77–2.58 (m, 3H), 2.39–2.33 ( m, 1H), 2.29 (s, 3H), 1.87–1.79 (m, 2H), 1.73–1.61 (m, 2H), 1.49 (m, 4H), 1.20–1.02 (m, 3H), 0.90–0.81 ( m,4H)ppm.

Example 114

synthetic route

Synthesis of compound 114-2

Compound 109-7 (0.16 g, 0.18 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 20 mL of 30% hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the obtained white solid was washed with 20 mL of ethyl acetate, and then the obtained solid was placed under vacuum to dry. The solid obtained after drying, compound 114-1 (0.02 g, 0.2 mmol), EDCI (0.04 g, 0.2 mmol) and HOAT (0.03 g, 0.2 mmol) were added to a round-bottomed flask, under nitrogen protection, 20 ml was added Dichloromethane was then cooled to 0°C and DIPEA (0.1 mL, 0.6 mmol) was added. After the addition was complete, the reaction mixture was warmed to 30°C and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL×3), and then the organic phases were combined. The organic phase was washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2 : 1) Purification to obtain white solid compound 114-2 (0.15 g, yield 89%).

MS(ESI, pos.ion) m/z: 922[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ) δ 10.41 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.45 (dd, J=8.4, 2.5 Hz, 1H), 7.42 (d, J= 2.2Hz, 1H), 7.37–7.34 (m, 2H), 7.32–7.29 (m, 1H), 7.27 (d, J=6.8Hz, 1H), 7.18 (d, J=8.3Hz, 1H), 7.13– 7.09(m, 2H), 6.97(d, J=8.8Hz, 2H), 6.69(d, J=2.3Hz, 1H), 6.02(s, 1H), 5.78–5.70(m, 1H), 5.05–4.98 (m, 1H), 4.69–4.60 (m, 3H), 4.49–4.43 (m, 1H), 4.11 (dd, J=11.3, 4.3Hz, 1H), 3.86 (s, 3H), 2.96–2.86 (m , 1H), 2.67–2.61 (m, 2H), 2.60–2.53 (m, 1H), 2.37 (q, J=8.6Hz, 1H), 2.07–2.03 (m, 1H), 1.94–1.90 (m, 2H ), 1.80–1.75 (m, 1H), 1.64–1.61 (m, 1H), 1.53–1.44 (m, 11H), 1.16–1.08 (m, 2H), 0.95–0.85 (m, 3H) ppm.

Example 115

synthetic route

Step 1: Synthesis of Compound 115-2

Compound 115-0 (2.7 g, 12 mmol), compound 115-1 (1.5 g, 11 mmol), H ₂ O (15 mL), toluene (30 mL), methanol (30 mL), potassium acetate (3 g, 21.5 mmol) and tetra (Triphenylphosphine)palladium (0.5 g, 0.4 mmol) was added to a round bottom flask. Under nitrogen, the reaction mixture was warmed to 100°C and stirred for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the organic solvent was spin-dried under reduced pressure. Then 50 mL of water and 50 mL of ethyl acetate were added to dilute, and then the liquids were separated. The aqueous phase was extracted twice with 50 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 50 mL of saturated brine, dried over anhydrous Na ₂ SO 4 , then filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain compound 115-2 as a pale yellow solid (2.0 g, yield: 79%).

Step 2: Synthesis of Compound 115-3

Compound 115-2 (2 g, 8.6 mmol), di-tert-butyl azodicarboxylate (3 g, 12.7 mmol), diphenyl-2-pyridinephosphine (3.5 g, 13 mmol) and isopropanol (4 mL, 6.1 mmol) were combined ) was dissolved in 100 mL of THF. The reaction mixture was stirred at room temperature for 8 hours, and after the reaction was complete, the organic solvent was removed under reduced pressure. The obtained residue was purified by silica gel column (petroleum ether:ethyl acetate (V:V)=10:1) to obtain compound 115-3 as a pale yellow solid (2.0 g, yield: 79%).

MS (ESI, pos.ion) m/z: 276.0 [M+H] ⁺ .

Step 3: Synthesis of Compound 115-5

Compound 115-3 (2.3 g, 8.4 mmol) and compound 115-4 (1.8 g, 11.0 mmol) were dissolved in 40 mL of DMF, and K ₂ CO ₃ (4 g, 28.6 mmol) was added thereto. After addition, the reaction mixture was The temperature was raised to 90°C for overnight reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 100 mL of EtOAc, washed with H ₂ O (50 mL×2), and washed with 50 mL of saturated brine once. The separated organic phase was dried over anhydrous Na ₂ SO ₄ and then filtered, and the obtained filtrate was concentrated under reduced pressure to obtain yellow solid compound 115-5 (3 g, yield: 84%).

MS (ESI, pos.ion) m/z: 426.2 [M+H] ⁺ .

Step 4: Synthesis of Compound 115-6

Compound 115-5 (3.2 g, 7.5 mmol) was dissolved in 60 mL of glacial acetic acid, and then reduced iron powder (2 g, 45 mmol) was added. The reaction mixture was heated to 115°C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature and the solid was removed by filtration. 100 mL of 1N HCl solution was added dropwise to the obtained filtrate, and a large amount of white solid was precipitated. After rinsing once, the obtained white solid was dried under vacuum to obtain compound 115-6 (2.7 g, yield: 99%) as a white solid, which was directly carried out to the next step without further purification.

MS(ESI, pos.ion) m/z: 364.1 [M+H] ⁺ .

Step 5: Synthesis of Compound 115-7

Compound 115-6 (0.5 g, 1 mmol) was added to 10 mL of toluene, under nitrogen protection, phosphorus oxychloride (0.5 mL, 5 mmol) was added, and N,N-dimethylaniline (0.1 mL, 0.8 mmol) was added slowly mmol). After the addition, the reaction mixture was heated to 110°C and reacted for 6 hours. After the reaction was complete, the reaction mixture was cooled to 0°C and the organic solvent was removed under reduced pressure. The resulting mixture was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V) =5:1) purification to give the product 115-7 as a pale yellow solid (0.472 g, 90% yield).

MS (ESI, pos.ion) m/z: 382.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 115-9

Potassium tert-butoxide (0.30 g, 3 mmol), compound 115-7 (0.47 g, 1.2 mmol) and compound 115-8 (0.5 g, 0.9 mmol) were added to 15 mL of anhydrous DMF, after the addition, the reaction mixture was The temperature was raised to 40° C. and stirred for 4 hours. After the reaction was completed, the reaction was quenched with 20 ml of water, and then the solution was separated. The aqueous phase was washed once with 20 ml of ethyl acetate, then adjusted to pH around 4 with 1N hydrochloric acid solution, extracted three times with 20 ml of ethyl acetate, and the organic phases were combined. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, then filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification to obtain white solid compound 115-9 (0.37 g, yield: 50%).

MS (ESI, pos.ion) m/z: 914.4 [M+H] ⁺ .

Step 7: Synthesis of Compounds 115-10

Compound 115-9 (0.19 g, 0.24 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 2 mL of 30% concentration of hydrochloric acid in ethyl acetate was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was filtered and the resulting white solid was rinsed with 5 mL of ethyl acetate and then dried in vacuo.

The dried solid, compound 5-methylisoxazole-3-carboxylic acid (0.04 g, 0.3 mmol), EDCI (0.13 g, 0.6 mmol) and HOAT (0.09 g, 0.66 mmol) were added to a round bottom flask, Then 10 mL of dichloromethane was added, cooled to 0°C, and DIPEA (0.2 mL, 1 mmol) was added. The reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, and extracted with dichloromethane (10 mL×2), and the organic phases were combined. The organic phase was washed once with 10 ml of saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)= 2:1) Purification gave compound 115-10 as a white solid (0.131 g, 86% yield).

MS(ESI, pos.ion) m/z: 923.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ): δ 10.48 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.47 (d, J = 2.1Hz, 1H), 7.33 (dd, J=8.3, 2.3Hz, 1H), 7.22–7.18 (m, 2H), 7.14 (dd, J=8.9, 4.6Hz, 1H), 7.09–7.05 (m, 1H), 6.96(d, J=8.7Hz, 2H), 6.22(s, 1H), 5.98(s, 1H), 5.76(dd, J=17.4, 9.2Hz, 1H), 5.01(dd, J=11.9 ,6.6Hz,1H),4.86–4.79(m,2H),4.67(t,J=8.1Hz,1H),4.59(dq,J=12.1,6.1Hz,1H),4.08(dd,J=11.5, 3.7Hz, 1H), 2.96–2.90 (m, 1H), 2.76–2.64 (m, 3H), 2.39–2.34 (m, 4H), 2.28–2.22 (m, 1H), 1.84 (dd, J=14.4, 7.0Hz, 2H), 1.67(t, J＝8.6Hz, 1H), 1.58-1.55(m, 1H), 1.53-1.47(m, 3H), 1.44(d, J＝11.9Hz, 2H), 1.38( d, J=4.6Hz, 4H), 1.21-1.05 (m, 3H), 0.96-0.88 (m, 3H) ppm.

Example 116

synthetic route

Step 1: Synthesis of Compound 116-2

Compound 116-1 (5 g, 30.101 mmol) was added to a round bottom flask, and thereto were added glacial acetic acid (50 mL) and concentrated sulfuric acid (10 mL). The reaction solution was heated to 100°C and stirred for 8 hours. After the reaction was completed, 100 mL of water was added to dilute, and then extracted with ethyl acetate (50 mL×3), and then the organic phases were combined. The organic phase was washed once with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure, and the crude product obtained was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V) =1:1) purification to obtain yellow solid compound 116-2 (3.5 g, yield 63%).

MS (ESI, pos.ion) m/z: 185.1 [M+H] ⁺ .

Step 2: Synthesis of Compound 116-3

Compound 116-2 (6.08g, 33.0mmol) was added to 100ml of toluene, then Lawson's reagent (6.88g, 16.5mmol) was added, the reaction solution was heated to 120°C and refluxed for 2 hours. After the reaction was completed, the reaction solution was cooled After reaching room temperature, the organic solvent was spin-dried under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain yellow solid compound 116-3 (5 g, yield 76%).

Step 3: Synthesis of Compound 116-4

Compound 116-3 (4.11 g, 20.5 mmol) was added to 100 mL of ethanol, and then 1-bromo-3-methyl-butan-2-one (6.21 g, 22.6 mmol) was added, and the reaction solution was refluxed for 10 hours. After completion, the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=10:1) to obtain yellow solid compound 116-4 (3 g, yield 55 %).

MS (ESI, pos.ion) m/z: 267.1 [M+H] ⁺ .

Step 4: Synthesis of Compound 116-6

Compound 116-5 (2.3 g, 14 mmol), compound 116-4 (3.3 g, 12 mmol) were dissolved in DMF (200 mL), and K ₂ CO ₃ (3.1 g, 22 mmol) was added thereto. After the addition was complete, the reaction mixture was warmed to 120°C for overnight reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, then 200 mL of water was added to quench the reaction, and then extracted with ethyl acetate (50 mL×3). The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain an orange oily liquid compound 116-6 (4.0 g, yield 78%), which was directly carried out to the next step reaction.

Step 5: Synthesis of Compound 116-7

The crude compound 116-6 (5 g, 12.01 mmol) obtained in step 4 was dissolved in glacial acetic acid (20 mL), and iron powder (3.3 g, 59 mmol) was added thereto. The reaction mixture was warmed to 110°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and filtered. The obtained filtrate was poured into 1N hydrochloric acid (50 mL) solution, a white solid was precipitated, then filtered, and the filter cake was washed with water, and the obtained solid was dried under vacuum to obtain yellow solid compound 116-7 (3 g, yield 71%).

MS (ESI, pos.ion) m/z: 354.9 [M+H] ⁺ .

Step 6: Synthesis of Compound 116-8

Compound 116-7 (3 g, 8.465 mmol) was added to toluene (100 mL), POCl ₃ (2.6 g, 17 mmol) and N,N-dimethylaniline (512 mg, 4.22 mmol) were slowly added under stirring. , the reaction mixture was refluxed for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent is petroleum ether) to obtain a pale yellow solid compound 116-8 (2.8 g, yield 89%). ).

MS (ESI, pos.ion) m/z: 372.8 [M+H] ⁺ .

Step 7: Synthesis of Compound 116-9

Compound 107-5 (686 mg, 1.206 mmol) was dissolved in DMF (50 mL), and thereto were added compound 116-8 (500 mg, 1.341 mmol) and potassium tert-butoxide (451 mg, 4.0192 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction, the pH value of the reaction mixture was adjusted to about 2-3 with 1N HCl aqueous solution, then diluted with 50 mL of water, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1 ) was purified to give compound 116-9 as a pale yellow solid (0.8 g, 70% yield).

MS (ESI, pos.ion) m/z: 905.4 [M+H] ⁺ .

Step 8: Synthesis of Compound 116-10

Compound 116-9 (500 mg, 0.55 mmol) was dissolved in 5N HCl ethyl acetate solution (10 mL), the reaction mixture was stirred at room temperature for 2 hours, after the reaction was completed, concentrated under reduced pressure to obtain white solid compound 116-10 (0.4 g, 90% yield).

Step 9: Synthesis of Compounds 116-11

Compound 116-10 (100 mg, 0.12 mmol) was dissolved in CH ₂ Cl ₂ (50 mL), and thereto were added compound 5-methylisoxazole-3-carboxylic acid (16 mg, 0.13 mmol), EDCI (27 mg, 0.14 mmol) and HOAT (19 mg, 0.14 mmol), under an ice bath, followed by the addition of DIPEA (47 mg, 0.36 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain a pale yellow solid compound 116-11 (0.09 g, 80% yield).

MS(ESI, pos.ion) m/z: 914.3 [M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ 10.44(s, 1H), 8.19(s, 1H), 7.96(s, 1H), 7.82(s, 1H), 7.75(d, J=8.1Hz, 1H) ,7.27–7.23(m,1H),7.20(d,J＝8.3Hz,1H),7.13(ddd,J＝15.9,11.1,6.4Hz,2H),6.88(s,1H),6.26(s,1H) ),6.02(s,1H),5.77(dd,J=17.2,8.9Hz,1H),5.11–4.97(m,1H),4.88–4.72(m,2H),4.65(t,J=8.0Hz, 1H), 4.09(d, J＝8.4Hz, 1H), 3.17(dt, J＝13.4, 6.7Hz, 1H), 2.93(d, J＝4.3Hz, 1H), 2.82–2.60(m, 3H), 2.45–2.29 (m, 4H), 2.27–2.18 (m, 1H), 1.89–1.83 (m, 2H), 1.69 (s, 1H), 1.58 (dd, J=8.7, 6.1Hz, 1H), 1.54– 1.43 (m, 4H), 1.37 (d, J=6.8Hz, 5H), 1.28 (s, 3H), 1.19–1.09 (m, 2H), 0.97–0.86 (m, 2H) ppm.

Example 117

synthetic route

Synthesis of Compound 117-1

Compound 109-7 (0.34 g, 0.38 mmol) was dissolved in 2 mL of ethyl acetate, cooled to 0° C., then 2 mL of 30% hydrochloric acid ethyl acetate solution was added, and the reaction solution was reacted at room temperature for two hours. After the reaction was complete, it was filtered, and the resulting white solid was washed with 20 mL of ethyl acetate, and then dried in vacuo.

The solid obtained after the above reaction was dried and compound 117-0 (0.1 g, 0.56 mmol), EDCI (0.10 g, 2.5 mmol) and HOAT (0.16 g, 2.5 mmol) were added to a round-bottomed flask, and 20 ml were added under nitrogen protection. Dichloromethane was then cooled to 0°C, DIPEA (0.5 mL, 10 mmol) was added and the reaction mixture was warmed to 30°C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, extracted with dichloromethane (20 mL×2), the organic phases were combined, the organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=2:1) to obtain compound 117-1 as a white solid (0.145 g, yield 39%).

MS(ESI, pos.ion) m/z: 923.3[M+H] ⁺ ;

¹ H NMR (600MHz, CDCl ₃ ) δ 10.46(s, 1H), 8.00(d, J=7.0Hz, 1H), 7.82(s, 1H), 7.68(s, 1H), 7.52(d, J= 8.5Hz, 2H), 7.46 (d, J=1.3Hz, 1H), 7.32 (dd, J=8.3, 1.9Hz, 1H), 7.20–7.13 (m, 4H), 6.97 (d, J=8.6Hz, 2H), 5.89(s, 1H), 5.74(dd, J＝17.7, 8.7Hz, 1H), 5.38(dt, J＝13.0, 6.4Hz, 1H), 5.05–4.98(m, 1H), 4.73(ddd , J=27.5, 21.8, 9.4Hz, 3H), 4.09 (dd, J=11.4, 3.6Hz, 1H), 3.85 (s, 3H), 2.94 (ddd, J=12.8, 8.1, 4.9Hz, 1H), 2.71–2.61 (m, 3H), 2.37 (dd, J=17.0, 8.4Hz, 1H), 2.09 (dd, J=20.0, 14.9Hz, 2H), 1.94–1.89 (m, 2H), 1.72 (s, 1H), 1.51 (ddd, J=41.3, 24.0, 7.9Hz, 8H), 1.39–1.35 (m, 2H), 1.18–1.09 (m, 3H), 0.96–0.87 (m, 3H) ppm.

Example 118

synthetic route

Step 1: Synthesis of Compound 118-1

Compound 99-3 (0.4 g, 0.6 mmol), compound 109-5 (4.25 g, 1.3 mmol), potassium tert-butoxide (0.3 g, 3 mmol) and DMF (20 mL) were added to the reaction flask, and the reaction solution was warmed to Stir overnight at 50°C. After the reaction was complete, 1 mol/L hydrochloric acid (20 mL) was added to quench the reaction, then ethyl acetate (20 mL) was added for extraction, and the layers were separated. The aqueous phase was extracted once with ethyl acetate (20 mL), the organic phases were combined, and saturated brine was used. Washed once, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=4:1) to obtain compound 118 as a pale yellow solid -1 (0.40 g, 60% yield).

MS(ESI,pos.ion)m/z:901.3[M+H] ⁺

Step 2: Synthesis of Compound 118-2

Compound 118-1 (0.3 g, 0.3 mmol) was dissolved in 2 mL of isopropanol, cooled to 0° C., then 5 mL of 40% concentration of hydrochloric acid in isopropanol was added, and the mixture was stirred at room temperature for two hours. After filtration, the resulting white solid was rinsed with 5 mL of ethyl acetate and the resulting solid was dried in vacuo.

The solid obtained after drying the above reaction, compound 5-methylisoxazole-3-carboxylic acid (0.1 g, 0.7 mmol), EDCI (0.2 g, 1 mmol) and HOAT (0.15 g, 1.1 mmol) were added to a round bottom flask , 20 mL of dichloromethane was added under nitrogen protection, then cooled to 0 °C, DIPEA (0.5 mL, 3 mmol) was added, the reaction mixture was warmed to 30 °C, and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, taken out with dichloromethane (20 mL×2), the organic phases were combined, the organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The organic solvent was removed, and the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 118-2 (0.081 g, yield 20%).

MS(ESI, pos.ion) m/z: 909.3[M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.32 (s, 1H), 8.14 (d, J=7.4 Hz, 1H), 7.93 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.46(s, 1H), 7.32(d, J=8.3Hz, 1H), 7.25–7.07(m, 4H), 6.98(d, J=8.5Hz, 2H), 6.24(s, 1H), 5.99(s ,1H),5.76(dd,J＝17.4,8.7Hz,1H),5.03(t,J＝9.3Hz,1H),4.81(d,J＝11.0Hz,2H),4.67(t,J＝8.0Hz ,1H),4.10(d,J＝8.0Hz,1H),3.89(d,J＝28.2Hz,3H),2.70(s,3H),2.38(s,3H),2.22(d,J＝10.4Hz , 2H), 1.88–1.75 (m, 3H), 1.53 (d, J=10.6Hz, 6H), 1.35 (d, J=5.2Hz, 2H), 0.99–0.65 (m, 6H) ppm.

Example 119

synthetic route

Step 1: Synthesis of Compound 119-1

Compound 99-3 (0.18 g, 0.31 mmol), compound 104-4 (0.14 g, 0.46 mmol), potassium tert-butoxide (0.15 g, 1.3 mmol) and DMF (20 mL) were added to the reaction flask, and the reaction solution was warmed to Stir overnight at 50°C. After the reaction was complete, 1 mol/L hydrochloric acid (20 mL) was added to quench the reaction, then ethyl acetate (20 mL) was added for extraction, and the layers were separated. The aqueous phase was extracted once with ethyl acetate (20 mL), the organic phases were combined, and saturated brine was used. Washed once, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=4:1) to obtain a pale yellow solid compound 119-1 (0.10 g, 40% yield).

MS (ESI, pos.ion) m/z: 852.9 [M+H] ⁺ .

Step 2: Synthesis of Compound 119-2

Compound 119-1 (0.1 g, 0.1 mmol) was dissolved in 2 mL of isopropanol, cooled to 0° C., and then 5 mL of 40% concentration of hydrochloric acid in isopropanol was added, and the reaction solution was stirred at room temperature for two hours. After the reaction was complete, it was filtered, the filter cake was rinsed with 5 mL of ethyl acetate, and the resulting solid was dried in vacuo.

The above dried solid, compound 5-methylisoxazole-3-carboxylic acid (0.05 g, 0.3 mmol), EDCI (0.07 g, 0.4 mmol) and HOAT (0.05 g, 0.4 mmol) were added to a round bottom flask , 20 mL of dichloromethane was added under nitrogen protection, then cooled to 0 °C, DIPEA (0.5 mL, 3 mmol) was added, the reaction mixture was warmed to 30 °C, and stirred for 6 hours. The reaction was quenched with 10 mL of water, extracted with dichloromethane (20 mL×2), the organic phases were combined, the organic phases were washed once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure, The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain white solid compound 119-2 (0.057 g, yield 50%).

MS(ESI, pos.ion) m/z: 861.7[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.09 (s, 2H), 7.34 (d, J=32.4 Hz, 1H), 7.22 (d, J=6.5 Hz, 1H), 7.15-6.98 (m, 4H) ),6.78(d,J=1.7Hz,1H),6.69–6.63(m,1H),6.26(s,1H),5.95(s,1H),5.74(dd,J=17.2,8.6Hz,1H) ,5.04(d,J＝9.5Hz,1H),4.80–4.65(m,3H),4.53(dd,J＝11.7,5.8Hz,1H),4.09(d,J＝9.0Hz,1H),3.76( s, 4H), 3.67(s, 2H), 3.61(s, 3H), 3.05(dd, J=136.9, 60.9Hz, 5H), 2.75–2.61(m, 4H), 2.39(s, 3H), 2.32 (d, J=8.7 Hz, 1H), 2.20 (d, J=11.7 Hz, 1H), 2.03 (dd, J=25.0, 18.3 Hz, 1H), 0.89 (t, J=6.6 Hz, 6H) ppm.

Example 120

synthetic route

Step 1: Synthesis of Compound 120-2

Compound 99-3 (0.4 g, 0.7 mmol), compound 120-1 (0.3 g, 1 mmol), potassium tert-butoxide (0.15 g, 1.3 mmol) and DMF (20 mL) were added to the reaction flask, and the temperature was raised to 50 °C and stirred overnight. After the reaction was completed, 1 mol/L hydrochloric acid (20 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The aqueous phase was extracted once with ethyl acetate (20 mL), the organic phases were combined, washed once with saturated brine, and anhydrous sulfuric acid. After drying over sodium, the obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=4:1) to obtain compound 120-2 as a pale yellow solid (0.35 g, yield 60%).

MS(ESI, pos.ion) m/z: 824.8 [M+H] ⁺ .

Step 2: Synthesis of Compound 120-3

Compound 120-2 (0.2 g, 0.3 mmol) was dissolved in 2 mL of isopropanol, cooled to 0°C, and then 5 mL of a 40% hydrochloric acid/isopropanol solution was added, and the reaction mixture was stirred at room temperature, The reaction ends when no gas is evolved. After completion of the reaction, the reaction mixture was filtered, and the obtained white solid was washed with 5 mL of ethyl acetate.

The solid obtained above, compound 5-methylisoxazole-3-carboxylic acid (0.08 g, 0.6 mmol), EDCI (0.14 g, 0.73 mmol) and HOAT (0.1 g, 0.7 mmol) were added to a round-bottomed flask under nitrogen. Protection, 20 mL of dichloromethane was added, then cooled to 0 °C, DIPEA (0.5 mL, 3 mmol) was added, the reaction mixture was warmed to 30 °C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with 10 mL of water, taken with dichloromethane (20 mL×2), the organic phases were combined, the organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V:V)=1:1) to obtain compound 120-3 as a white solid (0.165 g, yield 80%).

MS(ESI, pos.ion) m/z: 833.7[M+H] ⁺ ;

¹ H NMR (600 MHz, CDCl ₃ ) δ 10.37 (s, 1H), 8.36 (d, J=7.0 Hz, 1H), 8.17 (s, 1H), 7.16 (dd, J=8.3, 2.6 Hz, 1H) ,7.10–7.02(m,3H),6.79(d,J=2.7Hz,1H),6.68(dd,J=8.8,2.8Hz,1H),6.21(s,1H),5.95(s,1H), 5.75(dd,J＝17.4,8.9Hz,1H),5.01(t,J＝9.3Hz,1H),4.82(dd,J＝16.1,10.0Hz,2H),4.65(t,J＝8.1Hz,1H) ), 4.08(dd, J=11.3, 3.3Hz, 1H), 3.81(s, 3H), 2.77–2.64(m, 3H), 2.38–2.32(m, 4H), 2.29–2.24(m, 1H), 2.04 (d, J=14.5Hz, 1H), 1.83–1.76 (m, 3H), 1.65 (d, J=11.0Hz, 1H), 1.54–1.51 (m, 3H), 1.47–1.37 (m, 3H) , 1.31 (dd, J=25.1, 13.3 Hz, 3H), 0.94–0.75 (m, 3H) ppm.

biological activity

1) HCV NS3/4A protease inhibition assay

High-throughput screening of HCV NS3/4A protease inhibitors was performed using SensoLyte520HCV protease detection kit (Anaspec) based on fluorescence resonance energy transfer (FRET) technology. In the 5-FAM/QXL520 FRET substrate peptide, the fluorescence of 5-FAM was quenched by QXL520. 5-FAM/QXL ^TM 520FRET substrate peptide contains HCV NS3/4A protease cleavage site, can be cleaved into two independent fragments by HCV NS3/4A protease, the fluorescence recovery of 5-FAM, can be at Ex/Em=490/ Detected at 510 nm.

The inhibitory effect of the compound on HCV NS3/4A protease was evaluated by detecting the change of 5-FAM fluorescence signal intensity. The experimental process is briefly described as follows. The compounds were dissolved in DMSO, mixed well and prepared into a 10mM stock solution, diluted with DTT-containing Assay buffer, 1μM was used as the initial concentration of drug testing, 3-fold gradient dilution, 10 dilution points , take 3 μl of compound diluted in gradient and add it to 384-well plate, and the final concentration of DMSO in each well is 1%. Then, 3 μl of HCV NS3/4A recombinant protease genotype 1a (Anaspec) or HCV NS3/4A recombinant protease genotype 1b (Anaspec) was added to a 384-well plate at a final concentration of 0.25 ng/μl in each well. Set up positive compound controls, negative controls, and substrate controls. The 384-well plate was incubated in a 25°C incubator for 15 min for enzymatic reaction, and the substrate solution was incubated at the same temperature. After 15 minutes, 50-fold diluted FRET substrate peptide was added to each well, and the mixture was gently shaken for 1 minute to mix. Immediately placed in a PHERAstar FS multifunctional microplate reader (BMGLabtech), the fluorescence intensity was detected kinetically under the condition of Ex/Em=490/520 nm, and the data was recorded every 1 min, and the detection was continued for 30 min. The results were processed by GraphPad Prism software, and IC50 values of compounds for HCV NS3/4A enzyme inhibition were calculated. The _IC50 results of compounds against NS3/4A protease genotypes 1a and 1b are shown in Table 2.

Table 2

Example number 1a(nM) 1b(nM) Example number 1a(nM) 1b(nM) Example 2 3.6 N/A Example 16 38.4 N/A Example 3 1.7 N/A Example 17 69.2 35.6 Example 4 10.8 N/A Example 18 8.9 N/A Example 5 7.5 N/A Example 19 3.7 N/A Example 7 66.4 N/A Example 20 29.2 N/A Example 8 17.6 16.8 Example 21 6.3 N/A Example 9 1.9 N/A Example 22 6.7 N/A Example 10 4.4 N/A Example 23 14.8 N/A Example 11 12.5 N/A Example 24 16 N/A Example 12 7.3 14.3 Example 29 15.1 8.5 Example 13 4.8 N/A Example 30 15.6 N/A Example 14 6.5 12.3 Example 31 10.6 N/A Example 15 60.8 N/A Example 32 6.9 N/A

N/A: Indicates that no relevant monitoring has been carried out

2) HCV subgenomic replicon analysis

Activity of compounds was tested using two stably transduced cell lines with the HCV subgenomic replicon: one cell line derived from HCV genotype 1a and one cell line derived from HCV genotype 1b. The replicon structure is reported in Science, 1999, 285(5424): 110-3 and J. VIROL, 2003, 77(5): 3007-19. The replicon structure is a bicistronic subgenomic replicon, and the first cistron has a luciferase reporter and a neomycin phosphotransferase (neo) selectable marker. The second cistron is the HCV NS3-NS5B coding region to which adaptive mutations have been added. The HCV genotype 1a replicon NS3-NS5B coding region was derived from HCV strain H77 (1a-H77), with adaptive mutations E1202G, K1691R, K2040R and S2204I. HCV genotype 1b replicon NS3-NS5B coding region is derived from HCV Con1 strain (1b-Con1), with adaptive mutations E1202G, T1280I and S2204I.

The inhibitory effect of compounds on HCV replication was evaluated by detecting the activity of a luciferase reporter gene. The experimental method is briefly described as follows. Stably transfected cells Huh7-H77 and Huh7-Con1b containing HCV genotype 1a (1a-H77) and genotype 1b (1a-Con1) replicons were inoculated into a 96-well plate in a volume of 125 μl , at a density of 8000 cells/well. After 16-24 hours, the compound was diluted to an appropriate concentration by a 3-fold gradient dilution method with 11 dilution points, and the diluted compound was added to a 96-well plate with POD ^TM 810 microplate pretreatment system. The final concentration of DMSO is 0.5%. After incubation for 72 h at 37°C, 5% CO ₂ in a CO ₂ constant temperature culture, 40 μl of luciferase detection reagent (Promega Bright-Glo) was added to each well, and after 5 min, a chemiluminescence detection system (Envision) was used for detection . The experimental results were processed by GraphPad Prism software, and the EC50 of the compounds inhibiting the HCV replicon was calculated. The EC50 results of the compounds against HCV genotype la and genotype lb replicons are shown in Table 3.

table 3

Example number 1b(nM) 1a(nM) Example number 1b(nM) 1a(nM) Example 2 25.84 45.41 Example 36 14.22 25.89 Example 3 11.13 9.19 Example 37 62.79 54.78 Example 8 16.07 28.11 Example 44 18.2 60.3 Example 9 9.40 32.83 Example 47 67.4 44.4 Example 12 30.7 76.77 Example 52 32.1 47.3 Example 19 11.87 33.83 Example 56 40.3 37.8 Example 21 38.76 89.28 Example 66 26.3 23.5 Example 23 18.63 37.69 Example 67 7.3 13.5

Example 27 28.8 46.4 Example 68 22.2 7.4 Example 28 20.3 29.0

The IC ₅₀ results of the compounds for HCV NS3/4A protease inhibition and the EC ₅₀ results for HCV replicon inhibition, combined with the molecular docking simulation results, indicate that the compounds can specifically inhibit HCV NS3/4A protease and have good antiviral effects.

3) Rat PK screening test:

Test method: Take 250-300g male SD rats and divide them into two groups, 3 rats in each group. The compounds to be tested are administered to male rats by intravenous and intragastric administration, respectively, and blood is collected at 8 to 9 time points within 24 hours. A standard curve with a suitable range, using AB SCIEX API4000 or Agilent 6430 LC-MS/MS, in MRM mode to determine the concentration of the test compound in the plasma sample, and perform quantitative analysis. According to the drug concentration-time curve, the non-compartmental model method of WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters. The results of the PK experiments of the compounds in rats are shown in Table 4.

Table 4

N/A: Indicates that no relevant monitoring has been carried out

Conclusion: Compared with the reported compound (ABT-450), the compound of the present invention has obvious advantages in exposure, half-life and clearance rate.

It will be apparent to those skilled in the art that this disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from essential characteristics thereof. Accordingly, it is intended that the various embodiments be regarded in all respects as illustrative and non-restrictive, and reference should be made to the appended claims, rather than to the foregoing embodiments, and, therefore, within the meaning of equivalents of the appended claims and All variations within the scope are included herein.

In the description of this specification, reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., means a specific feature described in connection with the embodiment or example, A structure, material, or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and those of ordinary skill in the art will not depart from the principles and spirit of the present invention Variations, modifications, substitutions, and alterations to the above-described embodiments are possible without departing from the scope of the present invention, which is defined by the claims and their equivalents.

Claims (6)

1. A compound having the structure of one of the following:

or their pharmaceutically acceptable salts. 2. A pharmaceutical composition, wherein the pharmaceutical composition comprises the compound according to claim 1, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 3. The pharmaceutical composition according to claim 2, further comprising other anti-HCV drugs; wherein the anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, Compounds that promote the generation of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, Bavituximab, Civacir ^™ , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir ), danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK -8742), ombitasvir(ABT-267), neceprevir(ACH-2684), tegobuvir(GS-9190), grazoprevir(MK-5172), sovaprevir(ACH-1625), samatasvir(IDX-719), setrobuvir, veruprevir( ABT-450), erlotinib, simeprevir (TMC-435), asunaprevir (BMS-650032), vaniprevir (MK-7009), faldaprevir (BI-2013335), VX-135, CIGB-230, TG -2349, ABT-530, ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir(GS-9451), BZF-961, GS-9256, ANA975, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP- 013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-7 96, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-072, PF-00868554, BI-207127, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex Alpha-interferon, interferon gamma, or a combination thereof. 4. The pharmaceutical composition according to any one of claims 2-3, further comprising at least one HCV inhibitor; wherein the HCV inhibitor is used for inhibiting HCV replication process and inhibiting HCV viral protein function At least one; wherein the HCV replication process is selected from the complete viral cycle of HCV that HCV enters, uncoats, translates, replicates, assembles or releases; the HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B , NS5A or NS5B; and the internal ribosomal entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. 5. use of the compound according to claim 1 or the pharmaceutical composition according to any one of claims 2-4 in the preparation of a medicine for suppressing at least one of HCV replication and suppressing HCV viral protein function One; wherein the HCV replication process is selected from the complete viral cycle of HCV that HCV enters, uncoats, translates, replicates, assembles or releases; the HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A or NS5B; and the internal ribosomal entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication. 6. Use of the compound according to claim 1 or the pharmaceutical composition according to any one of claims 2-4 in the preparation of a medicament for preventing or treating HCV infection or hepatitis C in a patient disease.